Therapeutic agents useful for treating pain

ABSTRACT

A compound of formula: 
     
       
         
         
             
             
         
       
     
     wherein A, Ar, R 3 , R 6 , and m are disclosed herein, or a pharmaceutically acceptable salt thereof (a “Cyanoiminopiperazine Compound”), compositions comprising an effective amount of a Cyanoiminopiperazine Compound, and methods for treating or preventing pain, urinary incontinence, an ulcer, inflammatory-bowel disease, irritable-bowel syndrome, an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression in an animal comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound are disclosed.

This application is a division of U.S. application Ser. No. 10/607,563,filed Jun. 27, 2003, which claims the benefit of U.S. ProvisionalApplication No. 60/391,962, filed Jun. 28, 2002; U.S. ProvisionalApplication No. 60/411,030, filed Sep. 17, 2002; U.S. ProvisionalApplication No. 60/413,148, filed Sep. 25, 2002; and U.S. ProvisionalApplication No. 60/416,582, filed Oct. 8, 2002, each of which isincorporated herein by reference in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Cyanoiminopiperazine Compounds,compositions comprising an effective amount of a CyanoiminopiperazineCompound and methods for treating or preventing pain, urinaryincontinence (UI), an ulcer, inflammatory-bowel disease (IBD),irritable-bowel syndrome (IBS), an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, amyotrophic lateral sclerosis(ALS), dementia, retinopathy, a muscle spasm, a migraine, vomiting,dyskinesia or depression, comprising administering to an animal in needthereof an effective amount of a Cyanoiminopiperazine Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or cental nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at both Group I metabotropicglutamate receptors, i.e., metabotropic glutamate receptor 1 (“mGluR1”)and metabotropic glutamate receptor 5 (“mGluR5”) (M. E. Fundytus, CNSDrugs 15:29-58 (2001)), and vanilloid receptors (“VR1”) (V. Di Marzo etal., Current Opinion in Neurobiology 12:372-379 (2002)) to painprocessing. Inhibiting mGluR1 or mGluR5 reduces pain, as shown by invivo treatment with antibodies selective for either mGluR1 or mGluR5,where neuropathic pain in rats was attenuated (M. E. Fundytus et al.,NeuroReport 9:731-735 (1998)). It has also been shown that antisenseoligonucleotide knockdown of mGluR1 alleviates both neuropathic andinflammatory pain (M. E. Fundytus et al., British Journal ofPharmacology 132:354-367 (2001); M. E. Fundytus et al., Pharmacology,Biochemistry & Behavior 73:401-410 (2002)). Small molecule antagonistsfor mGluR5-attenuated pain in in vivo animal models are disclosed in,e.g., K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul etal., Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDAantagonists (e.g. ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.fluoxetine, sertraline and amitriptyline).

UI is uncontrollable urination, generally caused bybladder-detrusor-muscle instability. UI affects people of all ages andlevels of physical health, both in health care settings and in thecommunity at large. At present, UI afflicts 15-30% of elderly peopleliving at home, one-third of those living in acute-care settings, and atleast one-half of those living in long-term care institutions (R. M.Resnick, Lancet 346:94 (1995)). Persons having UI are predisposed toalso having urinary-tract infections, pressure ulcers, perineal rashesand urosepsis. Psychosocially, UI is associated with embarrassment,social stigmatization, depression and a risk of institutionalization(Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)). Economically,the costs of UI are great; in the United States alone, health-care costsassociated with UI are over $15 billion per annum.

Physiologic bladder contraction results in large part fromacetylcholine-induced stimulation of post-ganglionic muscarinic-receptorsites on bladder smooth muscle. Treatments for UI include theadministration of drugs having bladder-relaxant properties, which helpto control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI, however, hasachieved complete success in all classes of UI patients, nor hastreatment occurred without significant adverse side effects. Forexample, drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract hasbeen eroded by stomach acids or digestive juices. The sores aretypically well-defined round or oval lesions primarily occurring in thestomach and duodenum. About 1 in 10 people develop an ulcer. Ulcersdevelop as a result of an imbalance between acid-secretory factors, alsoknown as “aggressive factors,” such as stomach acid, pepsin, andHelicobacter pylori infection, and local mucosal-protective factors,such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansopraz are also usedto treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres toepithelial cells and is believed to form a protective coating at thebase of an ulcer to promote healing. Sucraflate, however, can causeconstipation, dry mouth, and interfere with the absorption of otherdrugs.

Antibiotics are used when Helicobacter pylori is the underlying cause ofthe ulcer. Often antibiotic therapy is coupled with the administrationof bismuth compounds such as bismuth subsalicylate and colloidal bismuthcitrate. The bismuth compounds are believed to enhance secretion ofmucous and HCO₃., inhibit pepsin activity, and act as an antibacterialagainst H. pylori. Ingestion of bismuth compounds, however, can lead toelevated plasma concentrations of Bi⁺³ and can interfere with theabsorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acidand stimulate the secretion of mucous and bicarbonate and are also usedto treat ulcers, especially ulcers in patients who require nonsteroidalanti-inflammatory drugs. Effective oral doses of prostaglandinanalogues, however, can cause diarrhea and abdominal cramping. Inaddition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers.Carbenoxolone appears to alter the composition and quantity of mucous,thereby enhancing the mucosal barrier. Carbenoxolone, however, can leadto Na⁺ and fluid retention, hypertension, hypokalemia, and impairedglucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapinecan also be used to reduce acid secretion and treat ulcers. Side effectsof muscarinic cholinergic antagonists include dry mouth, blurred vision,and constipation. The Merck Manual of Medical Information 496-500 (R.Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis ofTherapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

IBD is a chronic disorder in which the bowel becomes inflamed, oftencausing recurring abdominal cramps and diarrhea. The two types of IBDare Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominalpain, fever, loss of appetite, and weight loss. Complications associatedwith Crohn's disease include the development of intestinal obstructions,abnormal connecting channels (fistulas), and abscesses. The risk ofcancer of the large intestine is increased in people who have Crohn'sdisease. Often Crohn's disease is associated with other disorders suchas gallstones, inadequate absorption of nutrients, amyloidosis,arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyodermagangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primarysclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine. Generally, the drug is takenorally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptomsof Crohn's disease. The antibiotic metronidazole is often administeredwhen the disease affects the large intestine or causes abscesses andfistulas around the anus. Long-term use of metronidazole, however, candamage nerves, resulting in pins-and-needles sensations in the arms andlegs. Sulfasalazine and chemically related drugs can suppress mildinflammation, especially in the large intestine. These drugs, however,are less effective in sudden, severe flare-ups. Corticosteroids, such asprednisone, reduce fever and diarrhea and relieve abdominal pain andtenderness. Long-term corticosteroid therapy, however, invariablyresults in serious side effects such as high blood-sugar levels,increased risk of infection, osteoporosis, water retention, andfragility of the skin. Drugs such as azathioprine and mercaptourine cancompromise the immune system and are often effective for Crohn's diseasein patients that do not respond to other drugs. These drugs, however,usually need 3 to 6 months before they produce benefits and can causeserious side effects such as allergy, pancreatitis, and lowwhite-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely through out thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered. Sulfasalazine, olsalazie,prednisone, or mesalamine can be used to reduce inflammation.Azathioprine and mercaptopurine have been used to maintain remissions inulcerative-colitis patients who would otherwise need long-termcorticosteroid treatment. In severe cases of ulcerative colitis thepatient is hospitalized and given corticosteroids intravenously. Peoplewith severe rectal bleeding can require transfusions and intravenousfluids. If toxic colitis develops and treatments fail, surgery to removethe large intestine can be necessary. Non-emergency surgery can beperformed if cancer is diagnosed, precancerous legions are detected, orunremitting chronic disease would otherwise make the person an invalidor dependent on high doses of corticosteroids. Complete removal of thelarge intestine and rectum permanently cures ulcerative colitis. TheMerck Manual of Medical Information 530-532 (R. Berkow ed., 1997) andGoodman and Gilman's The Pharmacological Basis of Therapeutics (J.Hardman and L. Limbird eds., 9^(th) ed. 1996).

IBS is a disorder of motility of the entire gastrointestinal tract,causing abdominal pain, constipation, and/or diarrhea. IBS affectsthree-times more women than men. In IBS stimuli such as stress, diet,drugs, hormones, or irritants can cause the gastrointestinal tract tocontract abnormally. During an episode of IBS contractions of thegastrointestinal tract become stronger and more frequent, resulting inthe rapid transit of food and feces through the small intestine, oftenleading to diarrhea. Cramps result from the strong contractions of thelarge intestine and increased sensitivity of pain receptors in the largeintestine.

There are two major types of IBS. The first type, spastic-colon type, iscommonly triggered by eating, and usually produces periodic constipationand diarrhea with pain. Mucous often appears in the stool. The pain cancome in bouts of continuous dull aching pain or cramps, usually in thelower abdomen. The person suffering from spastic-colon type IBS can alsoexperience bloating, gas, nausea, headache, fatigue, depression,anxiety, and difficulty concentrating. The second type of IBS usuallyproduces painless diarrhea or constipation. The diarrhea can beginsuddenly and with extreme urgency. Often the diarrhea occurs soon aftera meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow ed., 1997).

Many drugs can cause physical and/or psychological addiction. Those mostwell known types of these drugs include opiates, such as heroin, opium,and morphine; sympathomimetics, including cocaine and amphetamines;sedative-hypnotics, including alcohol, benzodiazepines and barbiturates;and nicotine, which has effects similar to opioids and sympathomimetics.Drug addiction is characterized by a craving or compulsion for takingthe drug and an inability to limit its intake. Additionally, drugdependence is associated with drug tolerance, the loss of effect of thedrug following repeated administration, and withdrawal, the appearanceof physical and behavioral symptoms when the drug is not consumed.Sensitization occurs if repeated administration of a drug leads to anincreased response to each dose. Tolerance, sensitization, andwithdrawal are phenomena evidencing a change in the central nervoussystem resulting from continued use of the drug. This change canmotivate the addicted individual to continue consuming the drug despiteserious social, legal, physical and/or professional consequences. (See,e.g., U.S. Pat. No. 6,109,269 to Rise et al.).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the substance. U.S. Pat.No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiateagonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No.5,232,934 to Downs discloses administration of 3-phenoxypyridine totreat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato etal. disclose using a serotonin antagonist to treat chemical addiction.U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF orNT-4 growth factors to inhibit or reverse neurological adaptive changesthat correlate with behavioral changes in an addicted individual. U.S.Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenalmedullary cells into an animal's central nervous system to inhibit thedevelopment of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer etal. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies.

Parkinson's disease is a clinical syndrome comprising bradykinesia(slowness and poverty of movement), muscular rigidity, resting tremor(which usually abates during voluntary movement), and an impairment ofpostural balance leading to disturbance of gait and falling. Thefeatures of Parkinson's disease are a loss of pigmented, dopaminergicneurons of the substantia nigra pars compacta and the appearance ofintracellular inclusions known as Lewy bodies (Goodman and Gillman's ThePharmaceutical Basis of Therapeutics 506 (9^(th) ed. 1996)). Withouttreatment, Parkinson's disease progresses to a rigid akinetic state inwhich patients are incapable of caring for themselves. Death frequentlyresults from complications of immobility, including aspiration pneumoniaor pulmonary embolism. Drugs commonly used for the treatment ofParkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

Anxiety is a fear, apprehension, or dread of impending danger oftenaccompanied by restlessness, tension, tachycardia, and dyspnea. Othersymptoms commonly associated with anxiety include depression, especiallyaccompanied with dysthymic disorder (chronic “neurotic” depression);panic disorder; agoraphobia and other specific phobias; eatingdisorders; and many personality disorders. Often anxiety is unattachedto a clearly identified treatable primary illness. If a primary illnessis found, however, it can be desirable to deal with the anxiety at thesame time as the primary illness.

Currently, benzodiazepines are the most commonly used anti-anxietyagents for generalized anxiety disorder. Benzodiazepines, however, carrythe risk of producing impairment of cognition and skilled motorfunctions, particularly in the elderly, which can result in confusion,delerium, and falls with fractures. Sedatives are also commonlyprescribed for treating anxiety. The azapirones, such as buspirone, arealso used to treat moderate anxiety. The azapirones, however, are lessuseful for treating severe anxiety accompanied with panic attacks.

Epilepsy is a disorder characterized by the tendency to have recurringseizures. The etiology commonly consists of lesions in some part of thecortex, such as a tumor; developmental malformation; or damage due totrauma or stroke. In some cases the etiology is genetic. An epilepticseizure can be triggered by repetitive sounds, flashing lights, videogames, or touching certain parts of the body. Epilepsy is typicallytreated with anti-seizure drugs. In epilepsy cases, where anti-seizuredrugs are ineffective, and the defect in the brain is isolated to asmall area of the brain, surgical removal of that part of the brain canbe helpful in alleviating the seizures. In patients who have severalsources for the seizures or who have seizures that spread quickly to allparts of the brain, surgical removal of the nerve fibers that connectthe two sides of the brain can be helpful.

Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital,phenyloin, primidone, valproic acid, trimethadione, bemzodiaepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

A seizure is the result of abnormal electrical discharge in the brain.The discharge can involve a small area of the brain and lead to theperson only noticing an odd taste or smell or it can involve a largearea of the brain and lead to convulsions, i.e., a seizure that causesjerking and spasms of the muscles throughout the body. Convulsions canalso result in brief attacks of altered consciousness and loss ofconsciousness, muscle control, or bladder control. A seizures is oftenpreceded by auras, i.e., unusual sensations of smell, taste, or visionor an intense feeling that a seizure is about to begin. A seizuretypically lasts for about 2 to 5 minutes. When the seizure ends theperson can have headache, sore muscles, unusual sensations, confusion,and profound fatigue (postictal state). Usually the person cannotremember what happened during the seizure.

A stroke or cerebrovascular accident, is the death of brain tissue(cerebral infarction) resulting from the lack of blood flow andinsufficient oxygen to the brain. A stroke can be either ischemic orhemorrhagic. In an ischemic stroke, blood supply to the brain is cut offbecause of atherosclerosis or a blood clot that has blocked a bloodvessel. In a hemorrhagic stroke, a blood vessel bursts preventing normalblood flow and allowing blood to leak into an area of the brain anddestroying it. Most strokes develop rapidly and cause brain damagewithin minutes. In some cases, however, strokes can continue to worsenfor several hours or days. Symptoms of strokes vary depending on whatpart of the brain is effected. Symptoms include loss or abnormalsensations in an arm or leg or one side of the body, weakness orparalysis of an arm or leg or one side of the body, partial loss ofvison or hearing, double vision, dizziness, slurred speech, difficultyin thinking of the appropriate word or saying it, inability to recognizeparts of the body, unusual movements, loss of bladder control,imbalance, and falling, and fainting. The symptoms can be permanent andcan be associated with coma or stupor. Strokes can cause edema orswelling of the brain which can further damage brain tissue. For personssuffering from a stroke, intensive rehabilitation can help overcome thedisability caused by impairment of brain tissue. Rehabilitation trainsother parts of the brain to assume the tasks previously performed by thedamaged part.

Examples of drugs for treating strokes include anticoagulants such asheparin, drugs that break up clots such as streptokinase or tissueplasminogen activator, and drugs that reduce swelling such as mannitolor corticosteroids. The Merck Manual of Medical Information 352-355 (R.Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching. Prurituscan be attributed to dry skin, scabies, dermatitis, herpetiformis,atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites,pediculosis, contact dermatitis, drug reactions, urticaria, urticarialeruptions of pregnancy, psoriasis, lichen planus, lichen simplexchronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, andfiberglass dermatitis. Conventionally, pruritus is treated byphototherapy with ultraviolet B or PUVA or with therapeutic agents suchas naltrexone, nalmefene, danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292(2): 115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anxiolytic and anti-depressant activity in in vivo animal models(E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) andP. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37(2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4(9):873-74 (2001)).

International publication no. WO 02/16318 discloses a class ofN-cyanoimines allegedly useful for treating a acute pain, urinarybladder hypersensitiveness, an ulcer, IBD, and IBS.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, UI, an ulcer, IBD, IBS, an addictivedisorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke,a seizure, a pruritic condition, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia,or depression.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds having the formula (I):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is —(C₁-C₆)alkyl, or —O—(C₁-C₆)allyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃₋₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 3; and

m is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (Ia):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₃-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is:

-   -   (a)-naphthyl, —(C₁₄)aryl, or —(C₃-C₈)cycloalkyl each of which is        unsubstituted or substituted with one or more R⁷ groups; or    -   (b) pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl,        quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl,        benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,        pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,        thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or        quinazolinyl, each of which is substituted with one or more R⁷        groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₈)heterocycle, —C(halo)₃, CH₂(halo), —CH(halo)₂, —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 3; and

m is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (Ib):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently;

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R¹        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸H, —OR⁸, —COR⁸,—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁷, R⁹, and R¹⁰ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 3;

m is an integer ranging from 0 to 2; and

p is an integer ranging from 0 to 4.

The present invention encompasses compounds having the formula (Ic):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₁₀)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁹, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R¹² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

m is an integer ranging from 0 to 2; and

q is an integer ranging from 0 to 3.

The present invention also encompasses compounds having the formula(II):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₉-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₁-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is hydrogen, —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₁₋₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH—NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃₋₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(IIa):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is hydrogen, —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R¹² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups; and

each halo is independently —F, —Cl, —Br or —I;

q is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(III):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (IIIa):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₁-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is:

-   -   (a), -naphthyl, —(C₁₄)aryl, or —(C₃-C₈)cycloalkyl each of which        is unsubstituted or substituted with one or more R⁷ groups; or    -   (b) pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl,        quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl,        benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,        pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,        thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or        quinazolinyl, each of which is substituted with one or more R⁷        groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (IIIb):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂; or    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁷, R⁹, and R¹⁰ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 2;

m is an integer ranging from 0 to 2; and

p is an integer ranging from 0 to 4.

The present invention also encompasses compounds having the formula(IIIc):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;

(b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₁-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or

-   -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸,—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R¹² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups; each halo is independently —F, —Cl, —Br or —I;

q is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(IV):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₉-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is hydrogen, —(C₁-C₆)alkyl, or —O—(C₂-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I;

n is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula(IVa):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is hydrogen, —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR¹⁰H, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH(halo)_(p), —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR³, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R¹² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups; each halo is independently —F, —Cl, —Br or —I;

q is an integer ranging from 0 to 2; and

m is an integer ranging from 0 to 2.

The present invention also encompasses compounds having the formula (V):

and pharmaceutically acceptable salts thereof, wherein:

A is —NR⁴—, —O—, or —S—;

R¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl,        —(C₃-C₇)heterocycle, or —(C₇-C₁₀)bicycloheterocycle, each of        which is unsubstituted or substituted with one or more R⁵        groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each        of which is unsubstituted or substituted with one or more R⁷        groups;

R⁴ is hydrogen, —(C₁-C₆)alkyl, or —O—(C₁-C₆)alkyl;

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups;

each R⁷ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —CN, —OH, -halo,—N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂;

each halo is independently —F, —Cl, —Br or —I; and

m is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (VI):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₉-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R⁵ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstitute or        substituted with one or more R⁶ groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₉-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R⁵ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)        heteroaryl, each of which is unsubstituted or substituted with        one or more R⁶ groups;

each R⁴ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁶ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R⁷ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅₋₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R⁸ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇;

each R¹¹ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is 0 or 1;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5;

s is an integer ranging from 0 to 4; and

t is an integer ranging from 0 to 2.

The present invention encompasses compounds having the formula (VI):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R² is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R⁵ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstitute or        substituted with one or more R₆ groups;

each R³ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R⁵ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)        heteroaryl, each of which is unsubstituted or substituted with        one or more R⁶ groups;

each R⁴ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃₋₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR¹⁰H, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸;

each R⁶ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R⁷ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R⁸ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇;

each R¹¹ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)₂R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is 0 or 1;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5;

s is an integer ranging from 0 to 4; and

t is an integer ranging from 0 to 2.

A compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (III), (IIIa),(IIIb), (IIIc), (IV), (IVa), (V), (VI), or (VII), or a pharmaceuticallyacceptable salt thereof (a “Cyanoiminopiperazine Compound”) is usefulfor treating or preventing pain, UI, an ulcer, IBD, IBS, an addictivedisorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke,a seizure, a pruritic condition, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia,or depression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a Cyanoiminopiperazine Compound and a pharmaceuticallyacceptable carrier or excipient. The compositions are useful fortreating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a Cyanoiminopiperazine Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a Cyanoiminopiperazine Compound.

The invention still further relates to methods for inhibiting VanilloidReceptor 1 (“VR1”) function in a cell, comprising contacting a cellcapable of expressing VR1 with an effective amount of aCyanoiminopiperazine Compound.

The invention still further relates to methods for inhibiting mGluR5function in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a Cyanoiminopiperazine Compound.

The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a Cyanoiminopiperazine Compound.

The invention still further relates to a method for preparing acomposition, comprising the step of admixing a CyanoiminopiperazineCompound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Cyanoiminopiperazine Compound.

The present invention may be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 CyanoiminopiperazineCompounds of Formula (I)

As stated above, the present invention encompasses compounds of Formula(I)

and pharmaceutically acceptable salts thereof, where A, R¹, R², R³, R⁶,n, and m are defined above for the Cyanoiminopiperazine Compounds offormula (I).

In one embodiment n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, R¹ is halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₁-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₁-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups;

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₅-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In one embodiment, n and m are 0 and R⁶ is -phenyl. In anotherembodiment, n is 0, m is 1, R³ is methyl, and R⁶ is phenyl. In anotherembodiment, the -phenyl is substituted with a —(C₁-C₆) alkyl group. Inanother embodiment, the —(C₁-C₆) alkyl group is substituted at the4-position of the -phenyl. In another embodiment, the —(C₁-C₆) alkylgroup is a t-butyl group substituted at 4-position of the -phenyl. Inanother embodiment, the —(C₁-C₆) alkyl group is an iso-propyl groupsubstituted at the 4-position of the -phenyl.

In another embodiment, R¹ is —CF₃ or —CHF₂.

In another embodiment, n and m are 0 and R⁶ is -phenyl substituted atits 4-position with a —CF₃ group.

In another embodiment, n and m are 0, R₁ is -halo or methyl; and R⁶ is-phenyl. In one embodiment, -halo is —Cl. In another embodiment, the-phenyl is substituted with a —(C₁-C₆) alkyl group. In anotherembodiment, the —(C₁-C₆) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the —(C₁-C₆) alkyl group is at-butyl group or an iso-propyl group substituted at the 4-position ofthe -phenyl.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl substituted with —CF₃. In another embodiment, -halo is —Cl. Inanother embodiment, the —CF₃ is substituted at the 4-position of the-phenyl. In another embodiment, -halo is —Cl and the —CF₃ is substitutedat the 4-position of the -phenyl.

4.2 Cyanoiminopiperazine Compounds of Formula (IA)

The present invention also encompasses compounds of formula (Ia)

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³, R⁶,n, and m are defined above for the Cyanoiminopiperazine Compounds offormula (Ia).

In one embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₁-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -naphthyl, —(C₁₄)aryl, or—(C₃-C₈)cycloalkyl each of which is unsubstituted or substituted withone or more R⁷ groups.

In another embodiment, R⁶ is pyridyl, furyl, benzofuranyl, thiophenyl,benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl,imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, eachof which is substituted with one or more R⁷ groups.

In another embodiment, R⁶ is pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, or thiadiazolyl.

4.3 Cyanoiminopiperazine Compounds of Formula (IB)

The present invention encompasses compounds having the formula (Ib):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³, R⁹,R¹⁰, n, m, p and halo are defined above for the CyanoiminopiperazineCompounds of formula (Ib).

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, m is 0.

In another embodiment m is 1.

In another embodiment, m is 2.

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In one embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

4.4 Cyanoiminopiperazine Compounds of Formula (Ic)

The present invention encompasses compounds having the formula (Ic):

and pharmaceutically acceptable salts thereof, wherein A, R³, R⁶, R¹¹,R¹², m, and q are defined above for the Cyanoiminopiperazine Compoundsof formula (Ic).

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, q is 3.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂;or

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In another embodiment, R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH,—OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo).

In another embodiment, R¹¹ is -halo.

In another embodiment, R¹¹ is —Cl.

In another embodiment, R¹¹ is —Br.

In another embodiment, R¹¹ is —F.

In another embodiment, R¹¹ is —I.

In another embodiment, R¹¹ is —CH₃.

In another embodiment, q is 1 and R¹² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, q is 1 and R¹² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In one embodiment, q is 1 and R¹² is -phenyl, -naphthyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups.

4.5 Cyanoiminopiperazine Compounds of Formula (II)

The present invention also encompasses compounds of formula (II)

and pharmaceutically acceptable salts thereof, wherein A, R¹, R², R³,R⁶, n, and m are defined above for the Cyanoiminopiperazine Compounds offormula (II).

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, A is —NH—.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R¹ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In one embodiment, n and m are 0 and R⁶ is -phenyl. In anotherembodiment, n is 0, m is 1, R³ is methyl, and R⁶ is phenyl. In anotherembodiment, the -phenyl is substituted with a —(C₁-C₆) alkyl group. Inanother embodiment, the —(C₁-C₆) alkyl group is substituted at the4-position of the -phenyl. In another embodiment, the —(C₁-C₆) alkylgroup is a t-butyl group substituted at 4-position of the -phenyl. Inanother embodiment, the —(C₁-C₆) alkyl group is an iso-propyl groupsubstituted at the 4-position of the -phenyl.

In another embodiment, R¹ is —CF₃ or —CHF₂.

In another embodiment, n and m are 0 and R⁶ is -phenyl substituted atits 4-position with a —CF₃ group.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl. In one embodiment, -halo is —Cl. In another embodiment, the-phenyl is substituted with a —(C₁-C₆) alkyl group. In anotherembodiment, the —(C₁-C₆) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the —(C₁-C₆) alkyl group is at-butyl group or an iso-propyl group substituted at the 4-position ofthe -phenyl.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl substituted with —CF₃. In another embodiment, -halo is —Cl. Inanother embodiment, the —CF₃ is substituted at the 4-position of the-phenyl. In another embodiment, -halo is —Cl and the CF₃ is substitutedat the 4-position of the -phenyl.

4.6 Cyanoiminopiperazine Compounds of Formula (IIa)

The present invention also encompasses compounds having the formula(IIa):

and pharmaceutically acceptable salts thereof, wherein A, R³, R⁶, R¹¹,R¹², m, and q are defined above for the Cyanoiminopiperazine Compoundsof formula (IIa).

In one embodiment, q is 0.

In another embodiment q is 1.

In another embodiment q is 2.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₁-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In another embodiment, R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH,—OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo).

In another embodiment, R¹¹ is -halo.

In another embodiment, R¹¹ is —Cl.

In another embodiment, R¹¹ is —Br.

In another embodiment, R¹¹ is —F.

In another embodiment, R¹¹ is —I.

In another embodiment, R¹¹ is —CH₃.

In another embodiment, q is 1 and R¹² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, q is 1 and R¹² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, q is 1 and R¹² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

4.7 Cyanoiminopiperazine Compounds of Formula (III)

The present invention also encompasses compounds of formula (III)

and pharmaceutically acceptable salts thereof, wherein A, R¹, R², R³,R⁶, m, and n are defined above for the Cyanoiminopiperazine Compounds offormula (III).

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment, m is 0.

In one embodiment, m is 1.

In one embodiment, m is 2.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In one embodiment, A is —O—.

In one embodiment, A is —S—.

In one embodiment, R¹ is -halo.

In one embodiment, R¹ is —Cl.

In one embodiment, R¹ is —Br.

In one embodiment, R¹ is —I.

In one embodiment, R¹ is —F.

In one embodiment, R¹ is —CH₃.

In one embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In one embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In one embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups.

In one embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In one embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In one embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)aryl or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In one embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In one embodiment, R⁶ is -phenyl.

In one embodiment, n and m are 0 and R⁶ is -phenyl. In anotherembodiment,

n is 0, m is 1, R³ is methyl, and R⁶ is phenyl. In another embodiment,the -phenyl is substituted with a —(C₁-C₆) alkyl group. In anotherembodiment, the —(C₁-C₆) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the —(C₁-C₆) alkyl group is at-butyl group substituted at 4-position of the -phenyl. In anotherembodiment, the —(C₁-C₆) alkyl group is an iso-propyl group substitutedat the 4-position of the -phenyl.

In another embodiment, R¹ is —CF₃ or —CHF₂.

In another embodiment, n and m are 0 and R⁶ is -phenyl substituted atits 4-position with a —CF₃ group.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ isphenyl. In one embodiment, -halo is —Cl. In another embodiment, the-phenyl is substituted with a —(C₁-C₆) alkyl group. In anotherembodiment, the —(C₁-C₆) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the —(C₁-C₆) alkyl group is at-butyl group or an iso-propyl group substituted at the 4-position ofthe -phenyl.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl substituted with —CF₃. In another embodiment, -halo is —Cl. Inanother embodiment, the —CF₃ is substituted at the 4-position of the-phenyl. In another embodiment, -halo is —Cl and the —CF₃ is substitutedat the 4-position of the -phenyl.

4.8 Cyanoiminopiperazine Compounds of Formula (IIIa)

The present invention also encompasses compounds of formula (IIIa)

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³, R⁶,n, and m are defined above for the Cyanoiminopiperazine Compounds offormula (IIIa).

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups;

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂;or

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -naphthyl, —(C₁₄)aryl, or—(C₃-C₈)cycloalkyl each of which is unsubstituted or substituted withone or more R⁷ groups.

In another embodiment, R⁶ is pyridyl, furyl, benzofuranyl, thiophenyl,benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl,imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, eachof which is substituted with one or more R⁷ groups.

4.9 Cyanoiminopiperazine Compounds of Formula (IIIb)

The present invention encompasses compounds having the formula (IIIb):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³, R⁹,R¹⁰, n, m, and p are defined above for the CyanoiminopiperazineCompounds of formula (IIIb).

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In one embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, p is 3.

In another embodiment, p is 4.

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, n is 1 and R² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₁-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R¹ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R¹ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

4.10 Cyanoiminopiperazine Compounds of Formula (IIIc)

The present invention encompasses compounds having the formula (IIIc):

and pharmaceutically acceptable salts thereof, wherein A, R³, R⁶, R¹¹,R¹², m, and q are defined above for the Cyanoiminopiperazine Compoundsof formula (Ic).

In one embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₁-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₁-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In another embodiment, R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH,—OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo).

In another embodiment, R¹¹ is -halo.

In another embodiment, R¹¹ is —Cl.

In another embodiment, R¹¹ is —Br.

In another embodiment, R¹¹ is —F.

In another embodiment, R¹¹ is —I.

In another embodiment, R¹¹ is —CH₃.

In another embodiment, q is 1 and R¹² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, q is 1 and R¹² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, q is 1 and R¹² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₁-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

4.11 Cyanoiminopiperazine Compounds of Formula (IV)

The present invention also encompasses compounds of formula (IV):

and pharmaceutically acceptable salts thereof, where A, R¹, R², R³, R⁶,n, and m are defined above for the Cyanoiminopiperazine Compounds offormula (IV).

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —NH—.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, n is one and R² is -halo, —CN, —OH, —NO₂, or—NH₂;

In another embodiment, n is 1 and R² is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂₋₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, n is 1 and R² is -phenyl, -naphthyl, —(C₁₄)aryl,or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups;

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In one embodiment, n and m are 0 and R⁶ is -phenyl. In anotherembodiment, n is 0, m is 1, R³ is methyl, and R⁶ is phenyl. In anotherembodiment, the -phenyl is substituted with a —(C₁-C₆) alkyl group. Inanother embodiment, the —(C₁-C₆) alkyl group is substituted at the4-position of the -phenyl. In another embodiment, the —(C₁-C₆) alkylgroup is a t-butyl group substituted at 4-position of the -phenyl. Inanother embodiment, the —(C₁-C₆) alkyl group is an iso-propyl groupsubstituted at the 4-position of the -phenyl.

In another embodiment, R¹ is —CF₃ or —CHF₂.

In another embodiment, n and m are 0 and R⁶ is -phenyl substituted atits 4-position with a —CF₃ group.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl. In one embodiment, -halo is —Cl. In another embodiment, the-phenyl is substituted with a —(C₁-C₆) alkyl group. In anotherembodiment, the —(C₁-C₆) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the —(C₁-C₆) alkyl group is at-butyl group or an iso-propyl group substituted at the 4-position ofthe -phenyl.

In another embodiment, n and m are 0, R¹ is -halo or methyl; and R⁶ is-phenyl substituted with —CF₃. In another embodiment, -halo is —Cl. Inanother embodiment, the —CF₃ is substituted at the 4-position of the-phenyl. In another embodiment, -halo is —Cl and the —CF₃ is substitutedat the 4-position of the -phenyl.

4.12 Cyanoiminopiperazine Compounds of Formula (IVa)

The present invention also encompasses compounds having the formula(IVa):

and pharmaceutically acceptable salts thereof, wherein A, R³, R⁶, R¹¹,R¹², m and q are defined above for the Cyanoiminopiperazine Compounds offormula (IVa).

In one embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —NH—.

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₁-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R⁷ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, R⁶ is -phenyl.

In another embodiment, R¹¹ is -hydrogen, -halo, —CH₃, —NO₂, —CN, —OH,—OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo).

In another embodiment, R¹¹ is -halo.

In another embodiment, R¹¹ is —Cl.

In another embodiment, R¹¹ is —Br.

In another embodiment, R¹¹ is —F.

In another embodiment, R¹¹ is —I.

In another embodiment, R¹¹ is —CH₃.

In another embodiment, R¹² is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, R¹² is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, R¹² is -phenyl, -naphthyl, —(C₁₄)aryl, or—(C₁-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R¹ groups.

4.13 Cyanoiminopiperazine Compounds of Formula (V)

The present invention also encompasses compounds of formula (V)

and pharmaceutically acceptable salts thereof, wherein A, R¹, R³, R⁶,and m are defined above for the Cyanoiminopiperazine Compounds offormula (V).

In one embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, A is —NH—

In another embodiment, A is —N((C₁-C₆)alkyl)-.

In another embodiment, A is —N(O(C₁-C₆)alkyl)-.

In another embodiment, A is —O—.

In another embodiment, A is —S—.

In another embodiment, R¹ is -hydrogen.

In another embodiment, R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂,—C(halo)₃, —CH(halo)₂, or —CH₂(halo).

In another embodiment, R¹ is -halo.

In another embodiment, R¹ is —Cl.

In another embodiment, R¹ is —Br.

In another embodiment, R¹ is —I.

In another embodiment, R¹ is —F.

In another embodiment, R¹ is —CH₃.

In another embodiment, m is 1 and R³ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R³ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁷ groups.

In another embodiment, m is 1 and R³ is -phenyl, -naphthyl, —(C₁₄)arylor —(C₁-C₁₀)heteroaryl, each of which is unsubstituted or substitutedwith one or more R¹ groups.

In another embodiment, m is 1 and R³ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

In another embodiment, R⁶ is -phenyl, -naphthyl, —(C₃-C₈)cycloalkyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁵ groups.

In another embodiment, R⁶ is -phenyl.

In one embodiment, m is 0 and R⁶ is -phenyl. In another embodiment, m is1, R³ is methyl, and R⁶ is phenyl. In another embodiment, the -phenyl issubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is substituted at the 4-position of the -phenyl. Inanother embodiment, the —(C₁-C₆) alkyl group is a t-butyl groupsubstituted at 4-position of the -phenyl. In another embodiment, the—(C₁-C₆) alkyl group is an iso-propyl group substituted at the4-position of the -phenyl.

In another embodiment, R¹ is —CF₃ or —CHF₂.

In another embodiment, m is 0 and R⁶ is -phenyl substituted at its4-position with a —CF₃ group.

In another embodiment, m is 0, R¹ is -halo or methyl; and R⁶ is -phenyl.In one embodiment, -halo is —Cl. In another embodiment, the -phenyl issubstituted with a —(C₁-C₆) alkyl group. In another embodiment, the—(C₁-C₆) alkyl group is substituted at the 4-position of the -phenyl. Inanother embodiment, the —(C₁-C₆) alkyl group is a t-butyl group or aniso-propyl group substituted at the 4-position of the -phenyl.

In another embodiment, m is 0, R¹ is -halo or methyl; and R⁶ is -phenylsubstituted with —CF₃. In another embodiment, -halo is —Cl. In anotherembodiment, the —CF₃ is substituted at the 4-position of the -phenyl. Inanother embodiment, -halo is —Cl and the CF₃ is substituted at the4-position of the -phenyl.

4.14 Cyanoiminopiperazine Compounds of Formula (VI)

The present invention also encompasses compounds of formula (VI):

and pharmaceutically acceptable salts thereof, wherein Ar₁, Ar₂, R³, R⁴,m, and t are defined above for the Cyanoiminopiperazine Compound offormula (VI).

In one embodiment Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —Br.

In another embodiment, R₁ is —I.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃. In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, R₂ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or

In another embodiment, R₂ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered)heteroaryl, each of which is unsubstitute or substitutedwith one or more R₆ groups;

In another embodiment, R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, R₃ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₁-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.

In another embodiment, R₃ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered) heteroaryl, each of which is unsubstituted or substitutedwith one or more R₆ groups.

In another embodiment, R₃ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

4.15 Cyanoiminopiperazine Compounds of Formula (VII)

The present invention also encompasses compounds of formula (VII):

and pharmaceutically acceptable salts thereof, wherein Ar₁, Ar₂ R₃, R₄,m, and t are defined above for formula (VI).

In one embodiment Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —Br.

In another embodiment, R₁ is —I.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, R₂ is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or In another embodiment, R₂ is-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl, eachof which is unsubstitute or substituted with one or more R₆ groups;

In another embodiment, R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, R₃ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.

In another embodiment, R₃ is -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to10-membered) heteroaryl, each of which is unsubstituted or substitutedwith one or more R₆ groups.

In another embodiment, R₃ is —CH₃.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (R)-configuration.

In another embodiment, m is 1, R³ is —CH₃, and the carbon atom to whichthe —R³ is attached is in the (S)-configuration.

4.16 Cyanoiminopiperazine Compounds of Formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IIIb), (IIIc), (IV), (Iva), (V), (VI), and (VII)

Certain Cyanoiminopiperazine Compounds may have asymmetric centers andtherefore exist in different enantiomeric and diastereomic forms. Thisinvention relates to the use of all optical isomers and stereoisomers ofthe Cyanoiminopiperazine Compounds, and mixtures thereof, and to allpharmaceutical compositions and methods of treatment that may employ orcontain them.

In the Cyanoiminopiperazine Compounds each R³ can be on any carbon ofthe piperazine ring. In one embodiment, the CyanoiminopiperazineCompounds have only one R³ group, and that R³ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In anotherembodiment, the Cyanoiminopiperazine Compound has only one R³ group, andthat R³ group is attached to a carbon atom adjacent to the nitrogen atomattached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R)-phenyl.

In another embodiment, two R³ groups are on a single atom of thepiperazine ring. In another embodiment, an R³ group is attached to acarbon atom adjacent to the nitrogen atom attached to the pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group and anotherR³ group is attached to a carbon atom adjacent to the nitrogen atomattached to the —C(—N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl.

In another embodiment, the Cyanoiminopiperazine Compound has two R³groups, each being attached to a different carbon atom adjacent to anitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group. In another embodiment, theCyanoiminopiperazine Compound has two R³ groups, each being attached toa different carbon atom adjacent to a nitrogen atom attached to the—C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl.

In one embodiment, wherein the Cyanoiminopiperazine Compound has one ortwo R³ groups, the carbon atom to which an R³ group is attached has the(R) configuration.

In another embodiment, wherein the Cyanoiminopiperazine Compound has oneor two R³ groups, the carbon atom to which the R³ group is attached hasthe (S) configuration. In another embodiment, the CyanoiminopiperazineCompound has one or two R³ groups, and at least one of the carbon atomsto which an R³ group is attached has the (R) configuration. In anotherembodiment, the Cyanoiminopiperazine Compound has one or two R³ groups,and at least one of the carbon atoms to which an R³ group is attachedhas the (S) configuration.

In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, and the carbon to which the R³ groupis attached is in the (R) configuration. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (R) configuration,and R³ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cyanoiminopiperazine Compoundhas one or two R³ groups, an R³ group is attached to a carbon atomadjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, the carbon to which the R³ group isattached is in the (R) configuration, and R³ is —CH₃. In anotherembodiment, the Cyanoiminopiperazine Compound has one or two R³ groups,an R³ group is attached to a carbon atom adjacent to a nitrogen attachedto the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolylgroup, the carbon to which the R³ group is attached is in the (R)configuration, and R³ is —CF₃. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (R) configuration,and R¹ is —CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen atom attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R⁹)-phenyl, and the carbon to which the R³ group isattached is in the (R) configuration. In another embodiment, theCyanoiminopiperazine Compound has one, or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to the—C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (R) configuration, and R³ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethylgroup, —C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, thecarbon to which the R³ group is attached is in the (R) configuration,and R³ is —CH₃. In another embodiment, the Cyanoiminopiperazine Compoundhas one or two R³ groups, an R³ group is attached to a carbon atomadjacent to a nitrogen attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R)-phenyl, the carbon to which the R³ group is attached isin the (R) configuration, and R³ is —CF₃. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to the—C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (R) configuration, and R³ is—CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, and the carbon to which the R³ groupis attached is in the (S) configuration. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (S) configuration,and R³ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cyanoiminopiperazine Compoundhas one or two R³ groups, an R³ group is attached to a carbon atomadjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, the carbon to which the R³ group isattached is in the (S) configuration, and R³ is —CH₃. In anotherembodiment, the Cyanoiminopiperazine Compound has one or two R³ groups,an R³ group is attached to a carbon atom adjacent to a nitrogen attachedto the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolylgroup, the carbon to which the R³ group is attached is in the (S)configuration, and R³ is —CF₃. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (S) configuration,and R³ is —CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen atom attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R⁹)-phenyl, and the carbon to which the R³ group isattached is in the (S) configuration. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to the—C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (S) configuration, and R³ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the Cyanoiminopiperazine Compound has one or twoR³ groups, an R³ group is attached to a carbon atom adjacent to anitrogen attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethylgroup, —C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, thecarbon to which the R³ group is attached is in the (S) configuration,and R³ is —CH₃. In another embodiment, the Cyanoiminopiperazine

Compound has one or two R³ groups, an R³ group is attached to a carbonatom adjacent to a nitrogen attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R⁹)-phenyl, the carbon to which the R³ group is attachedis in the (S) configuration, and R³ is —CF₃. In another embodiment, theCyanoiminopiperazine Compound has one or two R³ groups, an R³ group isattached to a carbon atom adjacent to a nitrogen attached to the—C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (S) configuration, and R³ is—CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, orthiadiazolyl group, and the carbon to which the R³ group is attached isin the (R) configuration. In another embodiment, theCyanoiminopiperazine Compound has only one R³ group, the R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (R) configuration,and R³ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cyanoiminopiperazine Compoundhas only one R³ group, the R³ group is attached to a carbon atomadjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, the carbon to which the R³ group isattached is in the (R) configuration, and R³ is —CH₃. In anotherembodiment, the Cyanoiminopiperazine Compound has only one R³ group, theR³ group is attached to a carbon atom adjacent to a nitrogen attached tothe pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group,the carbon to which the R³ group is attached is in the (R)configuration, and R³ is —CF₃. In another embodiment, theCyanoiminopiperazine Compound has only one R³ group, the R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (R) configuration,and R³ is —CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenatom attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, and thecarbon to which the R³ group is attached is in the (R) configuration. Inanother embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (R) configuration, and R³ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (R) configuration, and R³ is—CH₃. In another embodiment, the Cyanoiminopiperazine Compound has onlyone R³ group, the R³ group is attached to a carbon atom adjacent to anitrogen attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethylgroup, —C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, thecarbon to which the R³ group is attached is in the (R) configuration,and R³ is —CF₃. In another embodiment, the Cyanoiminopiperazine Compoundhas only one R³ group, the R³ group is attached to a carbon atomadjacent to a nitrogen attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R⁹)-phenyl, the carbon to which the R³ group is attachedis in the (R) configuration, and R³ is —CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenatom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, orthiadiazolyl group, and the carbon to which the R³ group is attached isin the (S) configuration. In another embodiment, theCyanoiminopiperazine Compound has only one R³ group, the R³ group isattached to a carbon atom adjacent to a nitrogen attached to thepyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, thecarbon to which the R³ group is attached is in the (S) configuration,and R³ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cyanoiminopiperazine Compoundhas only one R³ group, the R³ group is attached to a carbon atomadjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, or thiadiazolyl group, the carbon to which the R³ group isattached is in the (S) configuration, and R³ is —CH₃. In anotherembodiment, the Cyanoiminopiperazine

Compound has only one R³ group, the R³ group is attached to a carbonatom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which theR³ group is attached is in the (S) configuration, and R³ is —CF₃. Inanother embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, orthiadiazolyl group, the carbon to which the R³ group is attached is inthe (S) configuration, and R³ is —CH₂CH₃.

In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenatom attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, and thecarbon to which the R³ group is attached is in the (S) configuration. Inanother embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (S) configuration, and R³ is—(C₁-C₄)alkyl unsubstituted or substituted with one or more halo groups.In another embodiment, the Cyanoiminopiperazine Compound has only one R³group, the R³ group is attached to a carbon atom adjacent to a nitrogenattached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethyl group,—C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, the carbonto which the R³ group is attached is in the (S) configuration, and R³ is—CH₃. In another embodiment, the Cyanoiminopiperazine Compound has onlyone R³ group, the R³ group is attached to a carbon atom adjacent to anitrogen attached to the —C(═N—CN)-A-R⁶ group, —C(═N—CN)—NH-phenethylgroup, —C(═N—CN)—NH-phenpropyl group, or —C(═N—CN)—NH—(R⁹)-phenyl, thecarbon to which the R³ group is attached is in the (S) configuration,and R³ is —CF₃. In another embodiment, the Cyanoiminopiperazine Compoundhas only one R³ group, the R³ group is attached to a carbon atomadjacent to a nitrogen attached to the —C(═N—CN)-A-R⁶ group,—C(═N—CN)—NH-phenethyl group, —C(═N—CN)—NH-phenpropyl group, or—C(═N—CN)—NH—(R⁹)-phenyl, the carbon to which the R³ group is attachedis in the (R) configuration, and R³ is —CH₂CH₃.

The present invention includes the Cyanoiminopiperazine Compounds, andthe pharmaceutically acceptable salts thereof, wherein one or morehydrogen, carbon or other atoms are replaced by isotopes thereof. Suchcompounds may be useful as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays.

Illustrative Cyanoiminopiperazine Compounds are listed below in Tables1-8:

TABLE 1 VI

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹AAA -2-(3-chloropyridyl) -t-butyl AAB -2-(3-chloropyridyl) -iso-butylAAC -2-(3-chloropyridyl) -sec-butyl AAD -2-(3-chloropyridyl) -cyclohexylAAE -2-(3-chloropyridyl) -t-butoxy AAF -2-(3-chloropyridyl) -isopropoxyAAG -2-(3-chloropyridyl) —CF₃ AAH -2-(3-chloropyridyl) —CH₂CF₃ AAI-2-(3-chloropyridyl) —OCF₃ AAJ -2-(3-chloropyridyl) —Cl AAK-2-(3-chloropyridyl) —Br AAL -2-(3-chloropyridyl) —I AAM-2-(3-chloropyridyl) -n-butyl AAN -2-(3-chloropyridyl) -n-propyl AAO-2-(3-fluoropyridyl) -t-butyl AAP -2-(3-fluoropyridyl) -iso-butyl AAQ-2-(3-fluoropyridyl) -sec-butyl AAR -2-(3-fluoropyridyl) -cyclohexyl AAS-2-(3-fluoropyridyl) -t-butoxy AAT -2-(3-fluoropyridyl) -isopropoxy AAU-2-(3-fluoropyridyl) —CF₃ AAV -2-(3-fluoropyridyl) —CH₂CF₃ AAW-2-(3-fluoropyridyl) —OCF₃ AAX -2-(3-fluoropyridyl) —Cl AAY-2-(3-fluoropyridyl) —Br AAZ -2-(3-fluoropyridyl) —I ABA-2-(3-fluoropyridyl) -n-butyl ABB -2-(3-fluoropyridyl) -n-propyl ABC-2-(3-methylpyridyl) -t-butyl ABD -2-(3-methylpyridyl) -iso-butyl ABE-2-(3-methylpyridyl) -sec-butyl ABF -2-(3-methylpyridyl) -cyclohexyl ABG-2-(3-methylpyridyl) -t-butoxy ABH -2-(3-methylpyridyl) -isopropoxy ABI-2-(3-methylpyridyl) —CF₃ ABJ -2-(3-methylpyridyl) —CH₂CF₃ ABK-2-(3-methylpyridyl) —OCF₃ ABL -2-(3-methylpyridyl) —Cl ABM-2-(3-methylpyridyl) —Br ABN -2-(3-methylpyridyl) —I ABO-2-(3-methylpyridyl) -n-butyl ABP -2-(3-methylpyridyl) -n-propyl ABQ-2-(3-CF₃-pyridyl) -t-butyl ABR -2-(3-CF₃-pyridyl) -iso-butyl ABS-2-(3-CF₃-pyridyl) -sec-butyl ABT -2-(3-CF₃-pyridyl) -cyclohexyl ABU-2-(3-CF₃-pyridyl) -t-butoxy ABV -2-(3-CF₃-pyridyl) -isopropoxy ABW-2-(3-CF₃-pyridyl) —CF₃ ABX -2-(3-CF₃-pyridyl) —CH₂CF₃ ABY-2-(3-CF₃-pyridyl) —OCF₃ ABZ -2-(3-CF₃-pyridyl) —Cl ACA-2-(3-CF₃-pyridyl) —Br ACB -2-(3-CF₃-pyridyl) —I ACC -2-(3-CF₃-pyridyl)-n-butyl ACD -2-(3-CF₃-pyridyl) -n-propyl ACE -2-(3-CHF₂-pyridyl)-t-butyl ACF -2-(3-CHF₂-pyridyl) -iso-butyl ACG -2-(3-CHF₂-pyridyl)-sec-butyl ACH -2-(3-CHF₂-pyridyl) -cyclohexyl ACl -2-(3-CHF₂-pyridyl)-t-butoxy ACJ -2-(3-CHF₂-pyridyl) -isopropoxy ACK -2-(3-CHF₂-pyridyl)—CF₃ ACL -2-(3-CHF₂-pyridyl) —CH₂CF₃ ACM -2-(3-CHF₂-pyridyl) —OCF₃ ACN-2-(3-CHF₂-pyridyl) —Cl ACO -2-(3-CHF₂-pyridyl) —Br ACP-2-(3-CHF₂-pyridyl) —I ACQ -2-(3-CHF₂-pyridyl) -n-butyl ACR-2-(3-CHF₂-pyridyl) -n-propyl ACS -2-(3-hydroxypyridyl) -t-butyl ACT-2-(3-hydroxypyridyl) -iso-butyl ACU -2-(3-hydroxypyridyl) -sec-butylACV -2-(3-hydroxypyridyl) -cyclohexyl ACW -2-(3-hydroxypyridyl)-t-butoxy ACX -2-(3-hydroxypyridyl) -isopropoxy ACY-2-(3-hydroxypyridyl) —CF₃ ACZ -2-(3-hydroxypyridyl) —CH₂CF₃ ADA-2-(3-hydroxypyridyl) —OCF₃ ADB -2-(3-hydroxypyridyl) —Cl ADC-2-(3-hydroxypyridyl) —Br ADD -2-(3-hydroxypyridyl) —I ADE-2-(3-hydroxypyridyl) -n-butyl ADF -2-(3-hydroxypyridyl) -n-propyl ADG-2-(3-nitropyridyl) -t-butyl ADH -2-(3-nitropyridyl) -iso-butyl ADI-2-(3-nitropyridyl) -sec-butyl ADJ -2-(3-nitropyridyl) -cyclohexyl ADK-2-(3-nitropyridyl) -t-butoxy ADL -2-(3-nitropyridyl) -isopropoxy ADM-2-(3-nitropyridyl) —CF₃ ADN -2-(3-nitropyridyl) —CH₂CF₃ ADO-2-(3-nitropyridyl) —OCF₃ ADP -2-(3-nitropyridyl) —Cl ADQ-2-(3-nitropyridyl) —Br ADR -2-(3-nitropyridyl) —I ADS-2-(3-nitropyridyl) -n-butyl ADT -2-(3-nitropyridyl) -n-propyl ADU-2-(3-cyanopyridyl) -t-butyl ADV -2-(3-cyanopyridyl) -iso-butyl ADW-2-(3-cyanopyridyl) -sec-butyl ADX -2-(3-cyanopyridyl) -cyclohexyl ADY-2-(3-cyanopyridyl) -t-butoxy ADZ -2-(3-cyanopyridyl) -isopropoxy AEA-2-(3-cyanopyridyl) —CF₃ AEB -2-(3-cyanopyridyl) —CH₂CF₃ AEC-2-(3-cyanopyridyl) —OCF₃ AED -2-(3-cyanopyridyl) —Cl AEE-2-(3-cyanopyridyl) —Br AEF -2-(3-cyanopyridyl) —I AEG-2-(3-cyanopyridyl) -n-butyl AEH -2-(3-cyanopyridyl) -n-propyl AEI-2-(3-bromopyridyl) -t-butyl AEJ -2-(3-bromopyridyl) -iso-butyl AEK-2-(3-bromopyridyl) -sec-butyl AEL -2-(3-bromopyridyl) -cyclohexyl AEM-2-(3-bromopyridyl) -t-butoxy AEN -2-(3-bromopyridyl) -isopropoxy AEO-2-(3-bromopyridyl) —CF₃ AEP -2-(3-bromopyridyl) —CH₂CF₃ AEQ-2-(3-bromopyridyl) —OCF₃ AER -2-(3-bromopyridyl) —Cl AES-2-(3-bromopyridyl) —Br AET -2-(3-bromopyridyl) —I AEU-2-(3-bromopyridyl) -n-butyl AEV -2-(3-bromopyridyl) -n-propyl AEW-2-(3-iodopyridyl) -t-butyl AEX -2-(3-iodopyridyl) -iso-butyl AEY-2-(3-iodopyridyl) -sec-butyl AEZ -2-(3-iodopyridyl) -cyclohexyl AFA-2-(3-iodopyridyl) -t-butoxy AFB -2-(3-iodopyridyl) -isopropoxy AFC-2-(3-iodopyridyl) —CF₃ AFD -2-(3-iodopyridyl) —CH₂CF₃ AFE-2-(3-iodopyridyl) —OCF₃ AFF -2-(3-iodopyridyl) —Cl AFG-2-(3-iodopyridyl) —Br AFH -2-(3-iodopyridyl) —I AFI -2-(3-iodopyridyl)-n-butyl AFJ -2-(3-iodopyridyl) -n-propyl AFK -4-(5-chloropyrimidinyl)-t-butyl AFL -4-(5-chloropyrimidinyl) -iso-butyl AFM-4-(5-chloropyrimidinyl) -sec-butyl AFN -4-(5-chloropyrimidinyl)-cyclohexyl AFO -4-(5-chloropyrimidinyl) -t-butoxy AFP-4-(5-chloropyrimidinyl) -isopropoxy AFQ -4-(5-chloropyrimidinyl) —CF₃AFR -4-(5-chloropyrimidinyl) —CH₂CF₃ AFS -4-(5-chloropyrimidinyl) —OCF₃AFT -4-(5-chloropyrimidinyl) —Cl AFU -4-(5-chloropyrimidinyl) —Br AFV-4-(5-chloropyrimidinyl) —I AFW -4-(5-chloropyrimidinyl) -n-butyl AFX-4-(5-chloropyrimidinyl) -n-propyl AFY -4-(5-methylpyrimidinyl) -t-butylAFZ -4-(5-methylpyrimidinyl) -iso-butyl AGA -4-(5-methylpyrimidinyl)-sec-butyl AGB -4-(5-methylpyrimidinyl) -cyclohexyl AGC-4-(5-methylpyrimidinyl) -t-butoxy AGD -4-(5-methylpyrimidinyl)-isopropoxy AGE -4-(5-methylpyrimidinyl) —CF₃ AGF-4-(5-methylpyrimidinyl) —CH₂CF₃ AGG -4-(5-methylpyrimidinyl) —OCF₃ AGH-4-(5-methylpyrimidinyl) —Cl AGI -4-(5-methylpyrimidinyl) —Br AGJ-4-(5-methylpyrimidinyl) —I AGK -4-(5-methylpyrimidinyl) -n-butyl AGL-4-(5-methylpyrimidinyl) -n-propyl AGM -4-(5-fluoropyrimidinyl) -t-butylAGN -4-(5-fluoropyrimidinyl) -iso-butyl AGO -4-(5-fluoropyrimidinyl)-sec-butyl AGP -4-(5-fluoropyrimidinyl) -cyclohexyl AGQ-4-(5-fluoropyrimidinyl) -t-butoxy AGR -4-(5-fluoropyrimidinyl)-isopropoxy AGS -4-(5-fluoropyrimidinyl) —CF₃ AGT-4-(5-fluoropyrimidinyl) —CH₂CF₃ AGU -4-(5-fluoropyrimidinyl) —OCF₃ AGV-4-(5-fluoropyrimidinyl) —Cl AGW -4-(5-fluoropyrimidinyl) —Br AGX-4-(5-fluoropyrimidinyl) —I AGY -4-(5-fluoropyrimidinyl) -n-butyl AGZ-4-(5-fluoropyrimidinyl) -n-propyl AHA -2-(3-chloropyrazinyl) -t-butylAHB -2-(3-chloropyrazinyl) -iso-butyl AHC -2-(3-chloropyrazinyl)-sec-butyl AHD -2-(3-chloropyrazinyl) -cyclohexyl AHE-2-(3-chloropyrazinyl) -t-butoxy AHF -2-(3-chloropyrazinyl) -isopropoxyAHG -2-(3-chloropyrazinyl) —CF₃ AHH -2-(3-chloropyrazinyl) —CH₂CF₃ AHI-2-(3-chloropyrazinyl) —OCF₃ AHJ -2-(3-chloropyrazinyl) —Cl AHK-2-(3-chloropyrazinyl) —Br AHL -2-(3-chloropyrazinyl) —I AHM-2-(3-chloropyrazinyl) -n-butyl AHN -2-(3-chloropyrazinyl) -n-propyl AHO-2-(3-methylpyrazinyl) -t-butyl AHP -2-(3-methylpyrazinyl) -iso-butylAHQ -2-(3-methylpyrazinyl) -sec-butyl AHR -2-(3-methylpyrazinyl)-cyclohexyl AHS -2-(3-methylpyrazinyl) -t-butoxy AHT-2-(3-methylpyrazinyl) -isopropoxy AHU -2-(3-methylpyrazinyl) —CF₃ AHV-2-(3-methylpyrazinyl) —CH₂CF₃ AHW -2-(3-methylpyrazinyl) —OCF₃ AHX-2-(3-methylpyrazinyl) —Cl AHY -2-(3-methylpyrazinyl) —Br AHZ-2-(3-methylpyrazinyl) —I AIA -2-(3-methylpyrazinyl) -n-butyl AIB-2-(3-methylpyrazinyl) -n-propyl AIC -2-(3-fluoropyrazinyl) -t-butyl AID-2-(3-fluoropyrazinyl) -iso-butyl AIE -2-(3-fluoropyrazinyl) -sec-butylAIF -2-(3-fluoropyrazinyl) -cyclohexyl AIG -2-(3-fluoropyrazinyl)-t-butoxy AIH -2-(3-fluoropyrazinyl) -isopropoxy AII-2-(3-fluoropyrazinyl) —CF₃ AIJ -2-(3-fluoropyrazinyl) —CH₂CF₃ AIK-2-(3-fluoropyrazinyl) —OCF₃ AIL -2-(3-fluoropyrazinyl) —Cl AIM-2-(3-fluoropyrazinyl) —Br AIN -2-(3-fluoropyrazinyl) —I AIO-2-(3-fluoropyrazinyl) -n-butyl AIP -2-(3-fluoropyrazinyl) -n-propyl AIQ-3-(4-chloropyridazinyl) -t-butyl AIR -3-(4-chloropyridazinyl)-iso-butyl AIS -3-(4-chloropyridazinyl) -sec-butyl AIT-3-(4-chloropyridazinyl) -cyclohexyl AIU -3-(4-chloropyridazinyl)-t-butoxy AIV -3-(4-chloropyridazinyl) -isopropoxy AIW-3-(4-chloropyridazinyl) —CF₃ AIX -3-(4-chloropyridazinyl) —CH₂CF₃ AIY-3-(4-chloropyridazinyl) —OCF₃ AIZ -3-(4-chloropyridazinyl) —Cl AJA-3-(4-chloropyridazinyl) —Br AJB -3-(4-chloropyridazinyl) —I AJC-3-(4-chloropyridazinyl) -n-butyl AJD -3-(4-chloropyridazinyl) -n-propylAJE -3-(4-methylpyridazinyl) -t-butyl AJF -3-(4-methylpyridazinyl)-iso-butyl AJG -3-(4-methylpyridazinyl) -sec-butyl AJH-3-(4-methylpyridazinyl) -cyclohexyl AJI -3-(4-methylpyridazinyl)-t-butoxy AJJ -3-(4-methylpyridazinyl) -isopropoxy AJK-3-(4-methylpyridazinyl) —CF₃ AJL -3-(4-methylpyridazinyl) —CH₂CF₃ AJM-3-(4-methylpyridazinyl) —OCF₃ AJN -3-(4-methylpyridazinyl) —Cl AJO-3-(4-methylpyridazinyl) —Br AJP -3-(4-methylpyridazinyl) —I AJQ-3-(4-methylpyridazinyl) -n-butyl AJR -3-(4-methylpyridazinyl) -n-propylAJS -3-(4-fluoropyridazinyl) -t-butyl AJT -3-(4-fluoropyridazinyl)-iso-butyl AJU -3-(4-fluoropyridazinyl) -sec-butyl AJV-3-(4-fluoropyridazinyl) -cyclohexyl AJW -3-(4-fluoropyridazinyl)-t-butoxy AJX -3-(4-fluoropyridazinyl) -isopropoxy AJY-3-(4-fluoropyridazinyl) —CF₃ AJZ -3-(4-fluoropyridazinyl) —CH₂CF₃ AKA-3-(4-fluoropyridazinyl) —OCF₃ AKB -3-(4-fluoropyridazinyl) —Cl AKC-3-(4-fluoropyridazinyl) —Br AKD -3-(4-fluoropyridazinyl) —I AKE-3-(4-fluoropyridazinyl) -n-butyl AKF -3-(4-fluoropyridazinyl) -n-propylAKG -5-(4-chlorothiadiazolyl) -t-butyl AKH -5-(4-chlorothiadiazolyl)-iso-butyl AKI -5-(4-chlorothiadiazolyl) -sec-butyl AKJ-5-(4-chlorothiadiazolyl) -cyclohexyl AKK -5-(4-chlorothiadiazolyl)-t-butoxy AKL -5-(4-chlorothiadiazolyl) -isopropoxy AKM-5-(4-chlorothiadiazolyl) —CF₃ AKN -5-(4-chlorothiadiazolyl) —CH₂CF₃ AKO-5-(4-chlorothiadiazolyl) —OCF₃ AKP -5-(4-chlorothiadiazolyl) —Cl AKQ-5-(4-chlorothiadiazolyl) —Br AKR -5-(4-chlorothiadiazolyl) —I AKS-5-(4-chlorothiadiazolyl) -n-butyl AKT -5-(4-chlorothiadiazolyl)-n-propyl AKU -5-(4-methylthiadiazolyl) -t-butyl AKV-5-(4-methylthiadiazolyl) -iso-butyl AKW -5-(4-methylthiadiazolyl)-sec-butyl AKX -5-(4-methylthiadiazolyl) -cyclohexyl AKY-5-(4-methylthiadiazolyl) -t-butoxy AKZ -5-(4-methylthiadiazolyl)-isopropoxy ALA -5-(4-methylthiadiazolyl) —CF₃ ALB-5-(4-methylthiadiazolyl) —CH₂CF₃ ALC -5-(4-methylthiadiazolyl) —OCF₃ALD -5-(4-methylthiadiazolyl) —Cl ALE -5-(4-methylthiadiazolyl) —Br ALF-5-(4-methylthiadiazolyl) —I ALG -5-(4-methylthiadiazolyl) -n-butyl ALH-5-(4-methylthiadiazolyl) -n-propyl ALI -5-(4-fluorothiadiazolyl)-t-butyl ALJ -5-(4-fluorothiadiazolyl) -iso-butyl ALK-5-(4-fluorothiadiazolyl) -sec-butyl ALL -5-(4-fluorothiadiazolyl)-cyclohexyl ALM -5-(4-fluorothiadiazolyl) -t-butoxy ALN-5-(4-fluorothiadiazolyl) -isopropoxy ALO -5-(4-fluorothiadiazolyl) —CF₃ALP -5-(4-fluorothiadiazolyl) —CH₂CF₃ ALQ -5-(4-fluorothiadiazolyl)—OCF₃ ALR -5-(4-fluorothiadiazolyl) —Cl ALS -5-(4-fluorothiadiazolyl)—Br ALT -5-(4-fluorothiadiazolyl) —I ALU -5-(4-fluorothiadiazolyl)-n-butyl ALV -5-(4-fluorothiadiazolyl) -n-propyl

TABLE 2 VII

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹ALW -2-(3-chloropyridyl) -t-butyl ALX -2-(3-chloropyridyl) -iso-butylALY -2-(3-chloropyridyl) -sec-butyl ALZ -2-(3-chloropyridyl) -cyclohexylAMA -2-(3-chloropyridyl) -t-butoxy AMB -2-(3-chloropyridyl) -isopropoxyAMC -2-(3-chloropyridyl) —CF₃ AMD -2-(3-chloropyridyl) —CH₂CF₃ AME-2-(3-chloropyridyl) —OCF₃ AMF -2-(3-chloropyridyl) —Cl AMG-2-(3-chloropyridyl) —Br AMH -2-(3-chloropyridyl) —I AMI-2-(3-chloropyridyl) -n-butyl AMJ -2-(3-chloropyridyl) -n-propyl AMK-2-(3-fluoropyridyl) -t-butyl AML -2-(3-fluoropyridyl) -iso-butyl AMM-2-(3-fluoropyridyl) -sec-butyl AMN -2-(3-fluoropyridyl) -cyclohexyl AMO-2-(3-fluoropyridyl) -t-butoxy AMP -2-(3-fluoropyridyl) -isopropoxy AMQ-2-(3-fluoropyridyl) —CF₃ AMR -2-(3-fluoropyridyl) —CH₂CF₃ AMS-2-(3-fluoropyridyl) —OCF₃ AMT -2-(3-fluoropyridyl) —Cl AMU-2-(3-fluoropyridyl) —Br AMV -2-(3-fluoropyridyl) —I AMW-2-(3-fluoropyridyl) -n-butyl AMX -2-(3-fluoropyridyl) -n-propyl AMY-2-(3-methylpyridyl) -t-butyl AMZ -2-(3-methylpyridyl) -iso-butyl ANA-2-(3-methylpyridyl) -sec-butyl ANB -2-(3-methylpyridyl) -cyclohexyl ANC-2-(3-methylpyridyl) -t-butoxy AND -2-(3-methylpyridyl) -isopropoxy ANE-2-(3-methylpyridyl) —CF₃ ANF -2-(3-methylpyridyl) —CH₂CF₃ ANG-2-(3-methylpyridyl) —OCF₃ ANH -2-(3-methylpyridyl) —Cl ANI-2-(3-methylpyridyl) —Br ANJ -2-(3-methylpyridyl) —I ANK-2-(3-methylpyridyl) -n-butyl ANL -2-(3-methylpyridyl) -n-propyl ANM-2-(3-CF₃-pyridyl) -t-butyl ANN -2-(3-CF₃-pyridyl) -iso-butyl ANO-2-(3-CF₃-pyridyl) -sec-butyl ANP -2-(3-CF₃-pyridyl) -cyclohexyl ANQ-2-(3-CF₃-pyridyl) -t-butoxy ANR -2-(3-CF₃-pyridyl) -isopropoxy ANS-2-(3-CF₃-pyridyl) —CF₃ ANT -2-(3-CF₃-pyridyl) —CH₂CF₃ ANU-2-(3-CF₃-pyridyl) —OCF₃ ANV -2-(3-CF₃-pyridyl) —Cl ANW-2-(3-CF₃-pyridyl) —Br ANX -2-(3-CF₃-pyridyl) —I ANY -2-(3-CF₃-pyridyl)-n-butyl ANZ -2-(3-CF₃-pyridyl) -n-propyl AOA -2-(3-CHF₂-pyridyl)-t-butyl AOB -2-(3-CHF₂-pyridyl) -iso-butyl AOC -2-(3-CHF₂-pyridyl)-sec-butyl AOD -2-(3-CHF₂-pyridyl) -cyclohexyl AOE -2-(3-CHF₂-pyridyl)-t-butoxy AOF -2-(3-CHF₂-pyridyl) -isopropoxy AOG -2-(3-CHF₂-pyridyl)—CF₃ AOH -2-(3-CHF₂-pyridyl) —CH₂CF₃ AOI -2-(3-CHF₂-pyridyl) —OCF₃ AOJ-2-(3-CHF₂-pyridyl) —Cl AOK -2-(3-CHF₂-pyridyl) —Br AOL-2-(3-CHF₂-pyridyl) —I AOM -2-(3-CHF₂-pyridyl) -n-butyl AON-2-(3-CHF₂-pyridyl) -n-propyl AOO -2-(3-hydroxypyridyl) -t-butyl AOP-2-(3-hydroxypyridyl) -iso-butyl AOQ -2-(3-hydroxypyridyl) -sec-butylAOR -2-(3-hydroxypyridyl) -cyclohexyl AOS -2-(3-hydroxypyridyl)-t-butoxy AOT -2-(3-hydroxypyridyl) -isopropoxy AOU-2-(3-hydroxypyridyl) —CF₃ AOV -2-(3-hydroxypyridyl) —CH₂CF₃ AOW-2-(3-hydroxypyridyl) —OCF₃ AOX -2-(3-hydroxypyridyl) —Cl AOY-2-(3-hydroxypyridyl) —Br AOZ -2-(3-hydroxypyridyl) —I APA-2-(3-hydroxypyridyl) -n-butyl APB -2-(3-hydroxypyridyl) -n-propyl APC-2-(3-nitropyridyl) -t-butyl APD -2-(3-nitropyridyl) -iso-butyl APE-2-(3-nitropyridyl) -sec-butyl APF -2-(3-nitropyridyl) -cyclohexyl APG-2-(3-nitropyridyl) -t-butoxy APH -2-(3-nitropyridyl) -isopropoxy API-2-(3-nitropyridyl) —CF₃ APJ -2-(3-nitropyridyl) —CH₂CF₃ APK-2-(3-nitropyridyl) —OCF₃ APL -2-(3-nitropyridyl) —Cl APM-2-(3-nitropyridyl) —Br APN -2-(3-nitropyridyl) —I APO-2-(3-nitropyridyl) -n-butyl APP -2-(3-nitropyridyl) -n-propyl APQ-2-(3-cyanopyridyl) -t-butyl APR -2-(3-cyanopyridyl) -iso-butyl APS-2-(3-cyanopyridyl) -sec-butyl APT -2-(3-cyanopyridyl) -cyclohexyl APU-2-(3-cyanopyridyl) -t-butoxy APV -2-(3-cyanopyridyl) -isopropoxy APW-2-(3-cyanopyridyl) —CF₃ APX -2-(3-cyanopyridyl) —CH₂CF₃ APY-2-(3-cyanopyridyl) —OCF₃ APZ -2-(3-cyanopyridyl) —Cl AQA-2-(3-cyanopyridyl) —Br AQB -2-(3-cyanopyridyl) —I AQC-2-(3-cyanopyridyl) -n-butyl AQD -2-(3-cyanopyridyl) -n-propyl AQE-2-(3-bromopyridyl) -t-butyl AQF -2-(3-bromopyridyl) -iso-butyl AQG-2-(3-bromopyridyl) -sec-butyl AQH -2-(3-bromopyridyl) -cyclohexyl AQI-2-(3-bromopyridyl) -t-butoxy AQJ -2-(3-bromopyridyl) -isopropoxy AQK-2-(3-bromopyridyl) —CF₃ AQL -2-(3-bromopyridyl) —CH₂CF₃ AQM-2-(3-bromopyridyl) —OCF₃ AQN -2-(3-bromopyridyl) —Cl AQO-2-(3-bromopyridyl) —Br AQP -2-(3-bromopyridyl) —I AQQ-2-(3-bromopyridyl) -n-butyl AQR -2-(3-bromopyridyl) -n-propyl AQS-2-(3-iodopyridyl) -t-butyl AQT -2-(3-iodopyridyl) -iso-butyl AQU-2-(3-iodopyridyl) -sec-butyl AQV -2-(3-iodopyridyl) -cyclohexyl AQW-2-(3-iodopyridyl) -t-butoxy AQX -2-(3-iodopyridyl) -isopropoxy AQY-2-(3-iodopyridyl) —CF₃ AQZ -2-(3-iodopyridyl) —CH₂CF₃ ARA-2-(3-iodopyridyl) —OCF₃ ARB -2-(3-iodopyridyl) —Cl ARC-2-(3-iodopyridyl) —Br ARD -2-(3-iodopyridyl) —I ARE -2-(3-iodopyridyl)-n-butyl ARF -2-(3-iodopyridyl) -n-propyl ARG -4-(5-chloropyrimidinyl)-t-butyl ARH -4-(5-chloropyrimidinyl) -iso-butyl ARI-4-(5-chloropyrimidinyl) -sec-butyl ARJ -4-(5-chloropyrimidinyl)-cyclohexyl ARK -4-(5-chloropyrimidinyl) -t-butoxy ARL-4-(5-chloropyrimidinyl) -isopropoxy ARM -4-(5-chloropyrimidinyl) —CF₃ARN -4-(5-chloropyrimidinyl) —CH₂CF₃ ARO -4-(5-chloropyrimidinyl) —OCF₃ARP -4-(5-chloropyrimidinyl) —Cl ARQ -4-(5-chloropyrimidinyl) —Br ARR-4-(5-chloropyrimidinyl) —I ARS -4-(5-chloropyrimidinyl) -n-butyl ART-4-(5-chloropyrimidinyl) -n-propyl ARU -4-(5-methylpyrimidinyl) -t-butylARV -4-(5-methylpyrimidinyl) -iso-butyl ARW -4-(5-methylpyrimidinyl)-sec-butyl ARX -4-(5-methylpyrimidinyl) -cyclohexyl ARY-4-(5-methylpyrimidinyl) -t-butoxy ARZ -4-(5-methylpyrimidinyl)-isopropoxy ASA -4-(5-methylpyrimidinyl) —CF₃ ASB-4-(5-methylpyrimidinyl) —CH₂CF₃ ASC -4-(5-methylpyrimidinyl) —OCF₃ ASD-4-(5-methylpyrimidinyl) —Cl ASE -4-(5-methylpyrimidinyl) —Br ASF-4-(5-methylpyrimidinyl) —I ASG -4-(5-methylpyrimidinyl) -n-butyl ASH-4-(5-methylpyrimidinyl) -n-propyl ASI -4-(5-fluoropyrimidinyl) -t-butylASJ -4-(5-fluoropyrimidinyl) -iso-butyl ASK -4-(5-fluoropyrimidinyl)-sec-butyl ASL -4-(5-fluoropyrimidinyl) -cyclohexyl ASM-4-(5-fluoropyrimidinyl) -t-butoxy ASN -4-(5-fluoropyrimidinyl)-isopropoxy ASO -4-(5-fluoropyrimidinyl) —CF₃ ASP-4-(5-fluoropyrimidinyl) —CH₂CF₃ ASQ -4-(5-fluoropyrimidinyl) —OCF₃ ASR-4-(5-fluoropyrimidinyl) —Cl ASS -4-(5-fluoropyrimidinyl) —Br AST-4-(5-fluoropyrimidinyl) —I ASU -4-(5-fluoropyrimidinyl) -n-butyl ASV-4-(5-fluoropyrimidinyl) -n-propyl ASW -2-(3-chloropyrazinyl) -t-butylASX -2-(3-chloropyrazinyl) -iso-butyl ASY -2-(3-chloropyrazinyl)-sec-butyl ASZ -2-(3-chloropyrazinyl) -cyclohexyl ATA-2-(3-chloropyrazinyl) -t-butoxy ATB -2-(3-chloropyrazinyl) -isopropoxyATC -2-(3-chloropyrazinyl) —CF₃ ATD -2-(3-chloropyrazinyl) —CH₂CF₃ ATE-2-(3-chloropyrazinyl) —OCF₃ ATF -2-(3-chloropyrazinyl) —Cl ATG-2-(3-chloropyrazinyl) —Br ATH -2-(3-chloropyrazinyl) —I ATI-2-(3-chloropyrazinyl) -n-butyl ATJ -2-(3-chloropyrazinyl) -n-propyl ATK-2-(3-methylpyrazinyl) -t-butyl ATL -2-(3-methylpyrazinyl) -iso-butylATM -2-(3-methylpyrazinyl) -sec-butyl ATN -2-(3-methylpyrazinyl)-cyclohexyl ATO -2-(3-methylpyrazinyl) -t-butoxy ATP-2-(3-methylpyrazinyl) -isopropoxy ATQ -2-(3-methylpyrazinyl) —CF₃ ATR-2-(3-methylpyrazinyl) —CH₂CF₃ ATS -2-(3-methylpyrazinyl) —OCF₃ ATT-2-(3-methylpyrazinyl) —Cl ATU -2-(3-methylpyrazinyl) —Br ATV-2-(3-methylpyrazinyl) —I ATW -2-(3-methylpyrazinyl) -n-butyl ATX-2-(3-methylpyrazinyl) -n-propyl ATY -2-(3-fluoropyrazinyl) -t-butyl ATZ-2-(3-fluoropyrazinyl) -iso-butyl AUA -2-(3-fluoropyrazinyl) -sec-butylAUB -2-(3-fluoropyrazinyl) -cyclohexyl AUC -2-(3-fluoropyrazinyl)-t-butoxy AUD -2-(3-fluoropyrazinyl) -isopropoxy AUE-2-(3-fluoropyrazinyl) —CF₃ AUF -2-(3-fluoropyrazinyl) —CH₂CF₃ AUG-2-(3-fluoropyrazinyl) —OCF₃ AUH -2-(3-fluoropyrazinyl) —Cl AUI-2-(3-fluoropyrazinyl) —Br AUJ -2-(3-fluoropyrazinyl) —I AUK-2-(3-fluoropyrazinyl) -n-butyl AUL -2-(3-fluoropyrazinyl) -n-propyl AUM-3-(4-chloropyridazinyl) -t-butyl AUN -3-(4-chloropyridazinyl)-iso-butyl AUO -3-(4-chloropyridazinyl) -sec-butyl AUP-3-(4-chloropyridazinyl) -cyclohexyl AUQ -3-(4-chloropyridazinyl)-t-butoxy AUR -3-(4-chloropyridazinyl) -isopropoxy AUS-3-(4-chloropyridazinyl) —CF₃ AUT -3-(4-chloropyridazinyl) —CH₂CF₃ AUU-3-(4-chloropyridazinyl) —OCF₃ AUV -3-(4-chloropyridazinyl) —Cl AUW-3-(4-chloropyridazinyl) —Br AUX -3-(4-chloropyridazinyl) —I AUY-3-(4-chloropyridazinyl) -n-butyl AUZ -3-(4-chloropyridazinyl) -n-propylAVA -3-(4-methylpyridazinyl) -t-butyl AVB -3-(4-methylpyridazinyl)-iso-butyl AVC -3-(4-methylpyridazinyl) -sec-butyl AVD-3-(4-methylpyridazinyl) -cyclohexyl AVE -3-(4-methylpyridazinyl)-t-butoxy AVF -3-(4-methylpyridazinyl) -isopropoxy AVG-3-(4-methylpyridazinyl) —CF₃ AVH -3-(4-methylpyridazinyl) —CH₂CF₃ AVI-3-(4-methylpyridazinyl) —OCF₃ AVJ -3-(4-methylpyridazinyl) —Cl AVK-3-(4-methylpyridazinyl) —Br AVL -3-(4-methylpyridazinyl) —I AVM-3-(4-methylpyridazinyl) -n-butyl AVN -3-(4-methylpyridazinyl) -n-propylAVO -3-(4-fluoropyridazinyl) -t-butyl AVP -3-(4-fluoropyridazinyl)-iso-butyl AVQ -3-(4-fluoropyridazinyl) -sec-butyl AVR-3-(4-fluoropyridazinyl) -cyclohexyl AVS -3-(4-fluoropyridazinyl)-t-butoxy AVT -3-(4-fluoropyridazinyl) -isopropoxy AVU-3-(4-fluoropyridazinyl) —CF₃ AVV -3-(4-fluoropyridazinyl) —CH₂CF₃ AVW-3-(4-fluoropyridazinyl) —OCF₃ AVX -3-(4-fluoropyridazinyl) —Cl AVY-3-(4-fluoropyridazinyl) —Br AVZ -3-(4-fluoropyridazinyl) —I AWA-3-(4-fluoropyridazinyl) -n-butyl AWB -3-(4-fluoropyridazinyl) -n-propylAWC -5-(4-chlorothiadiazolyl) -t-butyl AWD -5-(4-chlorothiadiazolyl)-iso-butyl AWE -5-(4-chlorothiadiazolyl) -sec-butyl AWF-5-(4-chlorothiadiazolyl) -cyclohexyl AWG -5-(4-chlorothiadiazolyl)-t-butoxy AWH -5-(4-chlorothiadiazolyl) -isopropoxy AWI-5-(4-chlorothiadiazolyl) —CF₃ AWJ -5-(4-chlorothiadiazolyl) —CH₂CF₃ AWK-5-(4-chlorothiadiazolyl) —OCF₃ AWL -5-(4-chlorothiadiazolyl) —Cl AWM-5-(4-chlorothiadiazolyl) —Br AWN -5-(4-chlorothiadiazolyl) —I AWO-5-(4-chlorothiadiazolyl) -n-butyl AWP -5-(4-chlorothiadiazolyl)-n-propyl AWQ -5-(4-methylthiadiazolyl) -t-butyl AWR-5-(4-methylthiadiazolyl) -iso-butyl AWS -5-(4-methylthiadiazolyl)-sec-butyl AWT -5-(4-methylthiadiazolyl) -cyclohexyl AWU-5-(4-methylthiadiazolyl) -t-butoxy AWV -5-(4-methylthiadiazolyl)-isopropoxy AWW -5-(4-methylthiadiazolyl) —CF₃ AWX-5-(4-methylthiadiazolyl) —CH₂CF₃ AWY -5-(4-methylthiadiazolyl) —OCF₃AWZ -5-(4-methylthiadiazolyl) —Cl AXA -5-(4-methylthiadiazolyl) —Br AXB-5-(4-methylthiadiazolyl) —I AXC -5-(4-methylthiadiazolyl) -n-butyl AXD-5-(4-methylthiadiazolyl) -n-propyl AXE -5-(4-fluorothiadiazolyl)-t-butyl AXF -5-(4-fluorothiadiazolyl) -iso-butyl AXG-5-(4-fluorothiadiazolyl) -sec-butyl AXH -5-(4-fluorothiadiazolyl)-cyclohexyl AXI -5-(4-fluorothiadiazolyl) -t-butoxy AXJ-5-(4-fluorothiadiazolyl) -isopropoxy AXK -5-(4-fluorothiadiazolyl) —CF₃AXL -5-(4-fluorothiadiazolyl) —CH₂CF₃ AXM -5-(4-fluorothiadiazolyl)—OCF₃ AXN -5-(4-fluorothiadiazolyl) —Cl AXO -5-(4-fluorothiadiazolyl)—Br AXP -5-(4-fluorothiadiazolyl) —I AXQ -5-(4-fluorothiadiazolyl)-n-butyl AXR -5-(4-fluorothiadiazolyl) -n-propyl

TABLE 3 VIII

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹AXS -2-(3-chloropyridyl) -t-butyl AXT -2-(3-chloropyridyl) -iso-butylAXU -2-(3-chloropyridyl) -sec-butyl AXV -2-(3-chloropyridyl) -cyclohexylAXW -2-(3-chloropyridyl) -t-butoxy AXX -2-(3-chloropyridyl) -isopropoxyAXY -2-(3-chloropyridyl) —CF₃ AXZ -2-(3-chloropyridyl) —CH₂CF₃ AYA-2-(3-chloropyridyl) —OCF₃ AYB -2-(3-chloropyridyl) —Cl AYC-2-(3-chloropyridyl) —Br AYD -2-(3-chloropyridyl) —I AYE-2-(3-chloropyridyl) -n-butyl AYF -2-(3-chloropyridyl) -n-propyl AYG-2-(3-fluoropyridyl) -t-butyl AYH -2-(3-fluoropyridyl) -iso-butyl AYI-2-(3-fluoropyridyl) -sec-butyl AYJ -2-(3-fluoropyridyl) -cyclohexyl AYK-2-(3-fluoropyridyl) -t-butoxy AYL -2-(3-fluoropyridyl) -isopropoxy AYM-2-(3-fluoropyridyl) —CF₃ AYN -2-(3-fluoropyridyl) —CH₂CF₃ AYO-2-(3-fluoropyridyl) —OCF₃ AYP -2-(3-fluoropyridyl) —Cl AYQ-2-(3-fluoropyridyl) —Br AYR -2-(3-fluoropyridyl) —I AYS-2-(3-fluoropyridyl) -n-butyl AYT -2-(3-fluoropyridyl) -n-propyl AYU-2-(3-methylpyridyl) -t-butyl AYV -2-(3-methylpyridyl) -iso-butyl AYW-2-(3-methylpyridyl) -sec-butyl AYX -2-(3-methylpyridyl) -cyclohexyl AYY-2-(3-methylpyridyl) -t-butoxy AYZ -2-(3-methylpyridyl) -isopropoxy AZA-2-(3-methylpyridyl) —CF₃ AZB -2-(3-methylpyridyl) —CH₂CF₃ AZC-2-(3-methylpyridyl) —OCF₃ AZD -2-(3-methylpyridyl) —Cl AZE-2-(3-methylpyridyl) —Br AZF -2-(3-methylpyridyl) —I AZG-2-(3-methylpyridyl) -n-butyl AZH -2-(3-methylpyridyl) -n-propyl AZI-2-(3-CF₃-pyridyl) -t-butyl AZJ -2-(3-CF₃-pyridyl) -iso-butyl AZK-2-(3-CF₃-pyridyl) -sec-butyl AZL -2-(3-CF₃-pyridyl) -cyclohexyl AZM-2-(3-CF₃-pyridyl) -t-butoxy AZN -2-(3-CF₃-pyridyl) -isopropoxy AZO-2-(3-CF₃-pyridyl) —CF₃ AZP -2-(3-CF₃-pyridyl) —CH₂CF₃ AZQ-2-(3-CF₃-pyridyl) —OCF₃ AZR -2-(3-CF₃-pyridyl) —Cl AZS-2-(3-CF₃-pyridyl) —Br AZT -2-(3-CF₃-pyridyl) —I AZU -2-(3-CF₃-pyridyl)-n-butyl AZV -2-(3-CF₃-pyridyl) -n-propyl AZW -2-(3-CHF₂-pyridyl)-t-butyl AZX -2-(3-CHF₂-pyridyl) -iso-butyl AZY -2-(3-CHF₂-pyridyl)-sec-butyl AZZ -2-(3-CHF₂-pyridyl) -cyclohexyl BAA -2-(3-CHF₂-pyridyl)-t-butoxy BAB -2-(3-CHF₂-pyridyl) -isopropoxy BAC -2-(3-CHF₂-pyridyl)—CF₃ BAD -2-(3-CHF₂-pyridyl) —CH₂CF₃ BAE -2-(3-CHF₂-pyridyl) —OCF₃ BAF-2-(3-CHF₂-pyridyl) —Cl BAG -2-(3-CHF₂-pyridyl) —Br BAH-2-(3-CHF₂-pyridyl) —I BAI -2-(3-CHF₂-pyridyl) -n-butyl BAJ-2-(3-CHF₂-pyridyl) -n-propyl BAK -2-(3-hydroxypyridyl) -t-butyl BAL-2-(3-hydroxypyridyl) -iso-butyl BAM -2-(3-hydroxypyridyl) -sec-butylBAN -2-(3-hydroxypyridyl) -cyclohexyl BAO -2-(3-hydroxypyridyl)-t-butoxy BAP -2-(3-hydroxypyridyl) -isopropoxy BAQ-2-(3-hydroxypyridyl) —CF₃ BAR -2-(3-hydroxypyridyl) —CH₂CF₃ BAS-2-(3-hydroxypyridyl) —OCF₃ BAT -2-(3-hydroxypyridyl) —Cl BAU-2-(3-hydroxypyridyl) —Br BAV -2-(3-hydroxypyridyl) —I BAW-2-(3-hydroxypyridyl) -n-butyl BAX -2-(3-hydroxypyridyl) -n-propyl BAY-2-(3-nitropyridyl) -t-butyl BAZ -2-(3-nitropyridyl) -iso-butyl BBA-2-(3-nitropyridyl) -sec-butyl BBB -2-(3-nitropyridyl) -cyclohexyl BBC-2-(3-nitropyridyl) -t-butoxy BBD -2-(3-nitropyridyl) -isopropoxy BBE-2-(3-nitropyridyl) —CF₃ BBF -2-(3-nitropyridyl) —CH₂CF₃ BBG-2-(3-nitropyridyl) —OCF₃ BBH -2-(3-nitropyridyl) —Cl BBI-2-(3-nitropyridyl) —Br BBJ -2-(3-nitropyridyl) —I BBK-2-(3-nitropyridyl) -n-butyl BBL -2-(3-nitropyridyl) -n-propyl BBM-2-(3-cyanopyridyl) -t-butyl BBN -2-(3-cyanopyridyl) -iso-butyl BBO-2-(3-cyanopyridyl) -sec-butyl BBP -2-(3-cyanopyridyl) -cyclohexyl BBQ-2-(3-cyanopyridyl) -t-butoxy BBR -2-(3-cyanopyridyl) -isopropoxy BBS-2-(3-cyanopyridyl) —CF₃ BBT -2-(3-cyanopyridyl) —CH₂CF₃ BBU-2-(3-cyanopyridyl) —OCF₃ BBV -2-(3-cyanopyridyl) —Cl BBW-2-(3-cyanopyridyl) —Br BBX -2-(3-cyanopyridyl) —I BBY-2-(3-cyanopyridyl) -n-butyl BBZ -2-(3-cyanopyridyl) -n-propyl BCA-2-(3-bromopyridyl) -t-butyl BCB -2-(3-bromopyridyl) -iso-butyl BCC-2-(3-bromopyridyl) -sec-butyl BCD -2-(3-bromopyridyl) -cyclohexyl BCE-2-(3-bromopyridyl) -t-butoxy BCF -2-(3-bromopyridyl) -isopropoxy BCG-2-(3-bromopyridyl) —CF₃ BCH -2-(3-bromopyridyl) —CH₂CF₃ BCI-2-(3-bromopyridyl) —OCF₃ BCJ -2-(3-bromopyridyl) —Cl BCK-2-(3-bromopyridyl) —Br BCL -2-(3-bromopyridyl) —I BCM-2-(3-bromopyridyl) -n-butyl BCN -2-(3-bromopyridyl) -n-propyl BCO-2-(3-iodopyridyl) -t-butyl BCP -2-(3-iodopyridyl) -iso-butyl BCQ-2-(3-iodopyridyl) -sec-butyl BCR -2-(3-iodopyridyl) -cyclohexyl BCS-2-(3-iodopyridyl) -t-butoxy BCT -2-(3-iodopyridyl) -isopropoxy BCU-2-(3-iodopyridyl) —CF₃ BCV -2-(3-iodopyridyl) —CH₂CF₃ BCW-2-(3-iodopyridyl) —OCF₃ BCX -2-(3-iodopyridyl) —Cl BCY-2-(3-iodopyridyl) —Br BCZ -2-(3-iodopyridyl) —I BDA -2-(3-iodopyridyl)-n-butyl BDB -2-(3-iodopyridyl) -n-propyl BDC -4-(5-chloropyrimidinyl)-t-butyl BDD -4-(5-chloropyrimidinyl) -iso-butyl BDE-4-(5-chloropyrimidinyl) -sec-butyl BDF -4-(5-chloropyrimidinyl)-cyclohexyl BDG -4-(5-chloropyrimidinyl) -t-butoxy BDH-4-(5-chloropyrimidinyl) -isopropoxy BDI -4-(5-chloropyrimidinyl) —CF₃BDJ -4-(5-chloropyrimidinyl) —CH₂CF₃ BDK -4-(5-chloropyrimidinyl) —OCF₃BDL -4-(5-chloropyrimidinyl) —Cl BDM -4-(5-chloropyrimidinyl) —Br BDN-4-(5-chloropyrimidinyl) —I BDO -4-(5-chloropyrimidinyl) -n-butyl BDP-4-(5-chloropyrimidinyl) -n-propyl BDQ -4-(5-methylpyrimidinyl) -t-butylBDR -4-(5-methylpyrimidinyl) -iso-butyl BDS -4-(5-methylpyrimidinyl)-sec-butyl BDT -4-(5-methylpyrimidinyl) -cyclohexyl BDU-4-(5-methylpyrimidinyl) -t-butoxy BDV -4-(5-methylpyrimidinyl)-isopropoxy BDW -4-(5-methylpyrimidinyl) —CF₃ BDX-4-(5-methylpyrimidinyl) —CH₂CF₃ BDY -4-(5-methylpyrimidinyl) —OCF₃ BDZ-4-(5-methylpyrimidinyl) —Cl BEA -4-(5-methylpyrimidinyl) —Br BEB-4-(5-methylpyrimidinyl) —I BEC -4-(5-methylpyrimidinyl) -n-butyl BED-4-(5-methylpyrimidinyl) -n-propyl BEE -4-(5-fluoropyrimidinyl) -t-butylBEF -4-(5-fluoropyrimidinyl) -iso-butyl BEG -4-(5-fluoropyrimidinyl)-sec-butyl BEH -4-(5-fluoropyrimidinyl) -cyclohexyl BEI-4-(5-fluoropyrimidinyl) -t-butoxy BEJ -4-(5-fluoropyrimidinyl)-isopropoxy BEK -4-(5-fluoropyrimidinyl) —CF₃ BEL-4-(5-fluoropyrimidinyl) —CH₂CF₃ BEM -4-(5-fluoropyrimidinyl) —OCF₃ BEN-4-(5-fluoropyrimidinyl) —Cl BEO -4-(5-fluoropyrimidinyl) —Br BEP-4-(5-fluoropyrimidinyl) —I BEQ -4-(5-fluoropyrimidinyl) -n-butyl BER-4-(5-fluoropyrimidinyl) -n-propyl BES -2-(3-chloropyrazinyl) -t-butylBET -2-(3-chloropyrazinyl) -iso-butyl BEU -2-(3-chloropyrazinyl)-sec-butyl BEV -2-(3-chloropyrazinyl) -cyclohexyl BEW-2-(3-chloropyrazinyl) -t-butoxy BEX -2-(3-chloropyrazinyl) -isopropoxyBEY -2-(3-chloropyrazinyl) —CF₃ BEZ -2-(3-chloropyrazinyl) —CH₂CF₃ BFA-2-(3-chloropyrazinyl) —OCF₃ BFB -2-(3-chloropyrazinyl) —Cl BFC-2-(3-chloropyrazinyl) —Br BFD -2-(3-chloropyrazinyl) —I BFE-2-(3-chloropyrazinyl) -n-butyl BFF -2-(3-chloropyrazinyl) -n-propyl BFG-2-(3-methylpyrazinyl) -t-butyl BFH -2-(3-methylpyrazinyl) -iso-butylBFI -2-(3-methylpyrazinyl) -sec-butyl BFJ -2-(3-methylpyrazinyl)-cyclohexyl BFK -2-(3-methylpyrazinyl) -t-butoxy BFL-2-(3-methylpyrazinyl) -isopropoxy BFM -2-(3-methylpyrazinyl) —CF₃ BFN-2-(3-methylpyrazinyl) —CH₂CF₃ BFO -2-(3-methylpyrazinyl) —OCF₃ BFP-2-(3-methylpyrazinyl) —Cl BFQ -2-(3-methylpyrazinyl) —Br BFR-2-(3-methylpyrazinyl) —I BFS -2-(3-methylpyrazinyl) -n-butyl BFT-2-(3-methylpyrazinyl) -n-propyl BFU -2-(3-fluoropyrazinyl) -t-butyl BFV-2-(3-fluoropyrazinyl) -iso-butyl BFW -2-(3-fluoropyrazinyl) -sec-butylBFX -2-(3-fluoropyrazinyl) -cyclohexyl BFY -2-(3-fluoropyrazinyl)-t-butoxy BFZ -2-(3-fluoropyrazinyl) -isopropoxy BGA-2-(3-fluoropyrazinyl) —CF₃ BGB -2-(3-fluoropyrazinyl) —CH₂CF₃ BGC-2-(3-fluoropyrazinyl) —OCF₃ BGD -2-(3-fluoropyrazinyl) —Cl BGE-2-(3-fluoropyrazinyl) —Br BGF -2-(3-fluoropyrazinyl) —I BGG-2-(3-fluoropyrazinyl) -n-butyl BGH -2-(3-fluoropyrazinyl) -n-propyl BGI-3-(4-chloropyridazinyl) -t-butyl BGJ -3-(4-chloropyridazinyl)-iso-butyl BGK -3-(4-chloropyridazinyl) -sec-butyl BGL-3-(4-chloropyridazinyl) -cyclohexyl BGM -3-(4-chloropyridazinyl)-t-butoxy BGN -3-(4-chloropyridazinyl) -isopropoxy BGO-3-(4-chloropyridazinyl) —CF₃ BGP -3-(4-chloropyridazinyl) —CH₂CF₃ BGQ-3-(4-chloropyridazinyl) —OCF₃ BGR -3-(4-chloropyridazinyl) —Cl BGS-3-(4-chloropyridazinyl) —Br BGT -3-(4-chloropyridazinyl) —I BGU-3-(4-chloropyridazinyl) -n-butyl BGV -3-(4-chloropyridazinyl) -n-propylBGW -3-(4-methylpyridazinyl) -t-butyl BGX -3-(4-methylpyridazinyl)-iso-butyl BGY -3-(4-methylpyridazinyl) -sec-butyl BGZ-3-(4-methylpyridazinyl) -cyclohexyl BHA -3-(4-methylpyridazinyl)-t-butoxy BHB -3-(4-methylpyridazinyl) -isopropoxy BHC-3-(4-methylpyridazinyl) —CF₃ BHD -3-(4-methylpyridazinyl) —CH₂CF₃ BHE-3-(4-methylpyridazinyl) —OCF₃ BHF -3-(4-methylpyridazinyl) —Cl BHG-3-(4-methylpyridazinyl) —Br BHH -3-(4-methylpyridazinyl) —I BHI-3-(4-methylpyridazinyl) -n-butyl BHJ -3-(4-methylpyridazinyl) -n-propylBHK -3-(4-fluoropyridazinyl) -t-butyl BHL -3-(4-fluoropyridazinyl)-iso-butyl BHM -3-(4-fluoropyridazinyl) -sec-butyl BHN-3-(4-fluoropyridazinyl) -cyclohexyl BHO -3-(4-fluoropyridazinyl)-t-butoxy BHP -3-(4-fluoropyridazinyl) -isopropoxy BHQ-3-(4-fluoropyridazinyl) —CF₃ BHR -3-(4-fluoropyridazinyl) —CH₂CF₃ BHS-3-(4-fluoropyridazinyl) —OCF₃ BHT -3-(4-fluoropyridazinyl) —Cl BHU-3-(4-fluoropyridazinyl) —Br BHV -3-(4-fluoropyridazinyl) —I BHW-3-(4-fluoropyridazinyl) -n-butyl BHX -3-(4-fluoropyridazinyl) -n-propylBHY -5-(4-chlorothiadiazolyl) -t-butyl BHZ -5-(4-chlorothiadiazolyl)-iso-butyl BIA -5-(4-chlorothiadiazolyl) -sec-butyl BIB-5-(4-chlorothiadiazolyl) -cyclohexyl BIC -5-(4-chlorothiadiazolyl)-t-butoxy BID -5-(4-chlorothiadiazolyl) -isopropoxy BIE-5-(4-chlorothiadiazolyl) —CF₃ BIF -5-(4-chlorothiadiazolyl) —CH₂CF₃ BIG-5-(4-chlorothiadiazolyl) —OCF₃ BIH -5-(4-chlorothiadiazolyl) —Cl BII-5-(4-chlorothiadiazolyl) —Br BIJ -5-(4-chlorothiadiazolyl) —I BIK-5-(4-chlorothiadiazolyl) -n-butyl BIL -5-(4-chlorothiadiazolyl)-n-propyl BIM -5-(4-methylthiadiazolyl) -t-butyl BIN-5-(4-methylthiadiazolyl) -iso-butyl BIO -5-(4-methylthiadiazolyl)-sec-butyl BIP -5-(4-methylthiadiazolyl) -cyclohexyl BIQ-5-(4-methylthiadiazolyl) -t-butoxy BIR -5-(4-methylthiadiazolyl)-isopropoxy BIS -5-(4-methylthiadiazolyl) —CF₃ BIT-5-(4-methylthiadiazolyl) —CH₂CF₃ BIU -5-(4-methylthiadiazolyl) —OCF₃BIV -5-(4-methylthiadiazolyl) —Cl BIW -5-(4-methylthiadiazolyl) —Br BIX-5-(4-methylthiadiazolyl) —I BIY -5-(4-methylthiadiazolyl) -n-butyl BIZ-5-(4-methylthiadiazolyl) -n-propyl BJA -5-(4-fluorothiadiazolyl)-t-butyl BJB -5-(4-fluorothiadiazolyl) -iso-butyl BJC-5-(4-fluorothiadiazolyl) -sec-butyl BJD -5-(4-fluorothiadiazolyl)-cyclohexyl BJE -5-(4-fluorothiadiazolyl) -t-butoxy BJF-5-(4-fluorothiadiazolyl) -isopropoxy BJG -5-(4-fluorothiadiazolyl) —CF₃BJH -5-(4-fluorothiadiazolyl) —CH₂CF₃ BJI -5-(4-fluorothiadiazolyl)—OCF₃ BJJ -5-(4-fluorothiadiazolyl) —Cl BJK -5-(4-fluorothiadiazolyl)—Br BJL -5-(4-fluorothiadiazolyl) —I BJM -5-(4-fluorothiadiazolyl)-n-butyl BJN -5-(4-fluorothiadiazolyl) -n-propyl

TABLE 4 IX

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹BJO (a and b) -2-(3-chloropyridyl) -t-butyl BJP (a and b)-2-(3-chloropyridyl) -iso-butyl BJQ (a and b) -2-(3-chloropyridyl)-sec-butyl BJR (a and b) -2-(3-chloropyridyl) -cyclohexyl BJS (a and b)-2-(3-chloropyridyl) -t-butoxy BJT (a and b) -2-(3-chloropyridyl)-isopropoxy BJU (a and b) -2-(3-chloropyridyl) —CF₃ BJV (a and b)-2-(3-chloropyridyl) —CH₂CF₃ BJW (a and b) -2-(3-chloropyridyl) —OCF₃BJX (a and b) -2-(3-chloropyridyl) —Cl BJY (a and b)-2-(3-chloropyridyl) —Br BJZ (a and b) -2-(3-chloropyridyl) —I BKA (aand b) -2-(3-chloropyridyl) -n-butyl BKB (a and b) -2-(3-chloropyridyl)-n-propyl BKC (a and b) -2-(3-fluoropyridyl) -t-butyl BKD (a and b)-2-(3-fluoropyridyl) -iso-butyl BKE (a and b) -2-(3-fluoropyridyl)-sec-butyl BKF (a and b) -2-(3-fluoropyridyl) -cyclohexyl BKG (a and b)-2-(3-fluoropyridyl) -t-butoxy BKH (a and b) -2-(3-fluoropyridyl)-isopropoxy BKI (a and b) -2-(3-fluoropyridyl) —CF₃ BKJ (a and b)-2-(3-fluoropyridyl) —CH₂CF₃ BKK (a and b) -2-(3-fluoropyridyl) —OCF₃BKL (a and b) -2-(3-fluoropyridyl) —Cl BKM (a and b)-2-(3-fluoropyridyl) —Br BKN (a and b) -2-(3-fluoropyridyl) —I BKO (aand b) -2-(3-fluoropyridyl) -n-butyl BKP (a and b) -2-(3-fluoropyridyl)-n-propyl BKQ (a and b) -2-(3-methylpyridyl) -t-butyl BKR (a and b)-2-(3-methylpyridyl) -iso-butyl BKS (a and b) -2-(3-methylpyridyl)-sec-butyl BKT (a and b) -2-(3-methylpyridyl) -cyclohexyl BKU (a and b)-2-(3-methylpyridyl) -t-butoxy BKV (a and b) -2-(3-methylpyridyl)-isopropoxy BKW (a and b) -2-(3-methylpyridyl) —CF₃ BKX (a and b)-2-(3-methylpyridyl) —CH₂CF₃ BKY (a and b) -2-(3-methylpyridyl) —OCF₃BKZ (a and b) -2-(3-methylpyridyl) —Cl BLA (a and b)-2-(3-methylpyridyl) —Br BLB (a and b) -2-(3-methylpyridyl) —I BLC (aand b) -2-(3-methylpyridyl) -n-butyl BLD (a and b) -2-(3-methylpyridyl)-n-propyl BLE (a and b) -2(3-CF₃-pyridyl) -t-butyl BLF (a and b)-2-(3-CF₃-pyridyl) -iso-butyl BLG (a and b) -2-(3-CF₃-pyridyl)-sec-butyl BLH (a and b) -2-(3-CF₃-pyridyl) -cyclohexyl BLI (a and b)-2-(3-CF₃-pyridyl) -t-butoxy BLJ (a and b) -2-(3-CF₃-pyridyl)-isopropoxy BLK (a and b) -2-(3-CF₃-pyridyl) —CF₃ BLL (a and b)-2-(3-CF₃-pyridyl) —CH₂CF₃ BLM (a and b) -2-(3-CF₃-pyridyl) —OCF₃ BLN (aand b) -2-(3-CF₃-pyridyl) —Cl BLO (a and b) -2-(3-CF₃-pyridyl) —Br BLP(a and b) -2-(3-CF₃-pyridyl) —I BLQ (a and b) -2-(3-CF₃-pyridyl)-n-butyl BLR (a and b) -2-(3-CF₃-pyridyl) -n-propyl BLS (a and b)-2-(3-CHF₂-pyridyl) -t-butyl BLT (a and b) -2-(3-CHF₂-pyridyl)-iso-butyl BLU (a and b) -2-(3-CHF₂-pyridyl) -sec-butyl BLV (a and b)-2-(3-CHF₂-pyridyl) -cyclohexyl BLW (a and b) -2-(3-CHF₂-pyridyl)-t-butoxy BLX (a and b) -2-(3-CHF₂-pyridyl) -isopropoxy BLY (a and b)-2-(3-CHF₂-pyridyl) —CF₃ BLZ (a and b) -2-(3-CHF₂-pyridyl) —CH₂CF₃ BMA(a and b) -2-(3-CHF₂-pyridyl) —OCF₃ BMB (a and b) -2-(3-CHF₂-pyridyl)—Cl BMC (a and b) -2-(3-CHF₂-pyridyl) —Br BMD (a and b)-2-(3-CHF₂-pyridyl) —I BME (a and b) -2-(3-CHF₂-pyridyl) -n-butyl BMF (aand b) -2-(3-CHF₂-pyridyl) -n-propyl BMG (a and b) -2-(3-hydroxypyridyl)-t-butyl BMH (a and b) -2-(3-hydroxypyridyl) -iso-butyl BMI (a and b)-2-(3-hydroxypyridyl) -sec-butyl BMJ (a and b) -2-(3-hydroxypyridyl)-cyclohexyl BMK (a and b) -2-(3-hydroxypyridyl) -t-butoxy BML (a and b)-2-(3-hydroxypyridyl) -isopropoxy BMM (a and b) -2-(3-hydroxypyridyl)—CF₃ BMN (a and b) -2-(3-hydroxypyridyl) —CH₂CF₃ BMO (a and b)-2-(3-hydroxypyridyl) —OCF₃ BMP (a and b) -2-(3-hydroxypyridyl) —Cl BMQ(a and b) -2-(3-hydroxypyridyl) —Br BMR (a and b) -2-(3-hydroxypyridyl)—I BMS (a and b) -2-(3-hydroxypyridyl) -n-butyl BMT (a and b)-2-(3-hydroxypyridyl) -n-propyl BMU (a and b) -2-(3-nitropyridyl)-t-butyl BMV (a and b) -2-(3-nitropyridyl) -iso-butyl BMW (a and b)-2-(3-nitropyridyl) -sec-butyl BMX (a and b) -2-(3-nitropyridyl)-cyclohexyl BMY (a and b) -2-(3-nitropyridyl) -t-butoxy BMZ (a and b)-2-(3-nitropyridyl) -isopropoxy BNA (a and b) -2-(3-nitropyridyl) —CF₃BNB (a and b) -2-(3-nitropyridyl) —CH₂CF₂ BNC (a and b)-2-(3-nitropyridyl) —OCF₃ BND (a and b) -2-(3-nitropyridyl) —Cl BNE (aand b) -2-(3-nitropyridyl) —Br BNF (a and b) -2-(3-nitropyridyl) —I BNG(a and b) -2-(3-nitropyridyl) -n-butyl BNH (a and b) -2-(3-nitropyridyl)-n-propyl BNI (a and b) -2-(3-cyanopyridyl) -t-butyl BNJ (a and b)-2-(3-cyanopyridyl) -iso-butyl BNK (a and b) -2-(3-cyanopyridyl)-sec-butyl BNL (a and b) -2-(3-cyanopyridyl) -cyclohexyl BNM (a and b)-2-(3-cyanopyridyl) -t-butoxy BNN (a and b) -2-(3-cyanopyridyl)-isopropoxy BNO (a and b) -2-(3-cyanopyridyl) —CF₃ BNP (a and b)-2-(3-cyanopyridyl) —CH₂CF₃ BNQ (a and b) -2-(3-cyanopyridyl) —OCF₃ BNR(a and b) -2-(3-cyanopyridyl) —Cl BNS (a and b) -2-(3-cyanopyridyl) —BrBNT (a and b) -2-(3-cyanopyridyl) —I BNU (a and b) -2-(3-cyanopyridyl)-n-butyl BNV (a and b) -2-(3-cyanopyridyl) -n-propyl BNW (a and b)-2-(3-bromopyridyl) -t-butyl BNX (a and b) -2-(3-bromopyridyl)-iso-butyl BNY (a and b) -2-(3-bromopyridyl) -sec-butyl BNZ (a and b)-2-(3-bromopyridyl) -cyclohexyl BOA (a and b) -2-(3-bromopyridyl)-t-butoxy BOB (a and b) -2-(3-bromopyridyl) -isopropoxy BOC (a and b)-2-(3-bromopyridyl) —CF₃ BOD (a and b) -2-(3-bromopyridyl) —CH₂CF₃ BOE(a and b) -2-(3-bromopyridyl) —OCF₃ BOF (a and b) -2-(3-bromopyridyl)—Cl BOG (a and b) -2-(3-bromopyridyl) —Br BOH (a and b)-2-(3-bromopyridyl) —I BOI (a and b) -2-(3-bromopyridyl) -n-butyl BOJ (aand b) -2-(3-bromopyridyl) -n-propyl BOK (a and b) -2-(3-iodopyridyl)-t-butyl BOL (a and b) -2-(3-iodopyridyl) -iso-butyl BOM (a and b)-2-(3-iodopyridyl) -sec-butyl BON (a and b) -2-(3-iodopyridyl)-cyclohexyl BOO (a and b) -2-(3-iodopyridyl) -t-butoxy BOP (a and b)-2-(3-iodopyridyl) -isopropoxy BOQ (a and b) -2-(3-iodopyridyl) —CF₃ BOR(a and b) -2-(3-iodopyridyl) —CH₂CF₃ BOS (a and b) -2-(3-iodopyridyl)—OCF₃ BOT (a and b) -2-(3-iodopyridyl) —Cl BOU (a and b)-2-(3-iodopyridyl) —Br BOV (a and b) -2-(3-iodopyridyl) —I BOW (a and b)-2-(3-iodopyridyl) -n-butyl BOX (a and b) -2-(3-iodopyridyl) -n-propylBOY (a and b) -4-(5-chloropyrimidinyl) -t-butyl BOZ (a and b)-4-(5-chloropyrimidinyl) -iso-butyl BPA (a and b)-4-(5-chloropyrimidinyl) -sec-butyl BPB (a and b)-4-(5-chloropyrimidinyl) -cyclohexyl BPC (a and b)-4-(5-chloropyrimidinyl) -t-butoxy BPD (a and b)-4-(5-chloropyrimidinyl) -isopropoxy BPE (a and b)-4-(5-chloropyrimidinyl) —CF₃ BPF (a and b) -4-(5-chloropyrimidinyl)—CH₂CF₃ BPG (a and b) -4-(5-chloropyrimidinyl) —OCF₃ BPH (a and b)-4-(5-chloropyrimidinyl) —Cl BPI (a and b) -4-(5-chloropyrimidinyl) —BrBPJ (a and b) -4-(5-chloropyrimidinyl) —I BPK (a and b)-4-(5-chloropyrimidinyl) -n-butyl BPL (a and b) -4-(5-chloropyrimidinyl)-n-propyl BPM (a and b) -4-(5-methylpyrimidinyl) -t-butyl BPN (a and b)-4-(5-methylpyrimidinyl) -iso-butyl BPO (a and b)-4-(5-methylpyrimidinyl) -sec-butyl BPP (a and b)-4-(5-methylpyrimidinyl) -cyclohexyl BPQ (a and b)-4-(5-methylpyrimidinyl) -t-butoxy BPR (a and b)-4-(5-methylpyrimidinyl) -isopropoxy BPS (a and b)-4-(5-methylpyrimidinyl) —CF₃ BPT (a and b) -4-(5-methylpyrimidinyl)—CH₂CF₃ BPU (a and b) -4-(5-methylpyrimidinyl) —OCF₃ BPV (a and b)-4-(5-methylpyrimidinyl) —Cl BPW (a and b) -4-(5-methylpyrimidinyl) —BrBPX (a and b) -4-(5-methylpyrimidinyl) —I BPY (a and b)-4-(5-methylpyrimidinyl) -n-butyl BPZ (a and b) -4-(5-methylpyrimidinyl)-n-propyl BQA (a and b) -4-(5-fluoropyrimidinyl) -t-butyl BQB (a and b)-4-(5-fluoropyrimidinyl) -iso-butyl BQC (a and b)-4-(5-fluoropyrimidinyl) -sec-butyl BQD (a and b)-4-(5-fluoropyrimidinyl) -cyclohexyl BQE (a and b)-4-(5-fluoropyrimidinyl) -t-butoxy BQF (a and b)-4-(5-fluoropyrimidinyl) -isopropoxy BQG (a and b)-4-(5-fluoropyrimidinyl) —CF₃ BQH (a and b) -4-(5-fluoropyrimidinyl)—CH₂CF₃ BQI (a and b) -4-(5-fluoropyrimidinyl) —OCF₃ BQJ (a and b)-4-(5-fluoropyrimidinyl) —Cl BQK (a and b) -4-(5-fluoropyrimidinyl) —BrBQL (a and b) -4-(5-fluoropyrimidinyl) —I BQM (a and b)-4-(5-fluoropyrimidinyl) -n-butyl BQN (a and b) -4-(5-fluoropyrimidinyl)-n-propyl BQO (a and b) -2-(3-chloropyrazinyl) -t-butyl BQP (a and b)-2-(3-chloropyrazinyl) -iso-butyl BQQ (a and b) -2-(3-chloropyrazinyl)-sec-butyl BQR (a and b) -2-(3-chloropyrazinyl) -cyclohexyl BQS (a andb) -2-(3-chloropyrazinyl) -t-butoxy BQT (a and b) -2-(3-chloropyrazinyl)-isopropoxy BQU (a and b) -2-(3-chloropyrazinyl) —CF₃ BQV (a and b)-2-(3-chloropyrazinyl) —CH₂CF₃ BQW (a and b) -2-(3-chloropyrazinyl)—OCF₃ BQX (a and b) -2-(3-chloropyrazinyl) —Cl BQY (a and b)-2-(3-chloropyrazinyl) —Br BQZ (a and b) -2-(3-chloropyrazinyl) —I BRA(a and b) -2-(3-chloropyrazinyl) -n-butyl BRB (a and b)-2-(3-chloropyrazinyl) -n-propyl BRC (a and b) -2-(3-methylpyrazinyl)-t-butyl BRD (a and b) -2-(3-methylpyrazinyl) -iso-butyl BRE (a and b)-2-(3-methylpyrazinyl) -sec-butyl BRF (a and b) -2-(3-methylpyrazinyl)-cyclohexyl BRG (a and b) -2-(3-methylpyrazinyl) -t-butoxy BRH (a and b)-2-(3-methylpyrazinyl) -isopropoxy BRI (a and b) -2-(3-methylpyrazinyl)—CF₃ BRJ (a and b) -2-(3-methylpyrazinyl) —CH₂CF₃ BRK (a and b)-2-(3-methylpyrazinyl) —OCF₃ BRL (a and b) -2-(3-methylpyrazinyl) —ClBRM (a and b) -2-(3-methylpyrazinyl) —Br BRN (a and b)-2-(3-methylpyrazinyl) —I BRO (a and b) -2-(3-methylpyrazinyl) -n-butylBRP (a and b) -2-(3-methylpyrazinyl) -n-propyl BRQ (a and b)-2-(3-fluoropyrazinyl) -t-butyl BRR (a and b) -2-(3-fluoropyrazinyl)-iso-butyl BRS (a and b) -2-(3-fluoropyrazinyl) -sec-butyl BRT (a and b)-2-(3-fluoropyrazinyl) -cyclohexyl BRU (a and b) -2-(3-fluoropyrazinyl)-t-butoxy BRV (a and b) -2-(3-fluoropyrazinyl) -isopropoxy BRW (a and b)-2-(3-fluoropyrazinyl) —CF₃ BRX (a and b) -2-(3-fluoropyrazinyl) —CH₂CF₃BRY (a and b) -2-(3-fluoropyrazinyl) —OCF₃ BRZ (a and b)-2-(3-fluoropyrazinyl) —Cl BSA (a and b) -2-(3-fluoropyrazinyl) —Br BSB(a and b) -2-(3-fluoropyrazinyl) —I BSC (a and b) -2-(3-fluoropyrazinyl)-n-butyl BSD (a and b) -2-(3-fluoropyrazinyl) -n-propyl BSE (a and b)-3-(4-chloropyridazinyl) -t-butyl BSF (a and b) -3-(4-chloropyridazinyl)-iso-butyl BSG (a and b) -3-(4-chloropyridazinyl) -sec-butyl BSH (a andb) -3-(4-chloropyridazinyl) -cyclohexyl BSI (a and b)-3-(4-chloropyridazinyl) -t-butoxy BSJ (a and b)-3-(4-chloropyridazinyl) -isopropoxy BSK (a and b)-3-(4-chloropyridazinyl) —CF₃ BSL (a and b) -3-(4-chloropyridazinyl)—CH₂CF₃ BSM (a and b) -3-(4-chloropyridazinyl) —OCF₃ BSN (a and b)-3-(4-chloropyridazinyl) —Cl BSO (a and b) -3-(4-chloropyridazinyl) —BrBSP (a and b) -3-(4-chloropyridazinyl) —I BSQ (a and b)-3-(4-chloropyridazinyl) -n-butyl BSR (a and b) -3-(4-chloropyridazinyl)-n-propyl BSS (a and b) -3-(4-methylpyridazinyl) -t-butyl BST (a and b)-3-(4-methylpyridazinyl) -iso-butyl BSU (a and b)-3-(4-methylpyridazinyl) -sec-butyl BSV (a and b)-3-(4-methylpyridazinyl) -cyclohexyl BSW (a and b)-3-(4-methylpyridazinyl) -t-butoxy BSX (a and b)-3-(4-methylpyridazinyl) -isopropoxy BSY (a and b)-3-(4-methylpyridazinyl) —CF₃ BSZ (a and b) -3-(4-methylpyridazinyl)—CH₂CF₃ BTA (a and b) -3-(4-methylpyridazinyl) —OCF₃ BTB (a and b)-3-(4-methylpyridazinyl) —Cl BTC (a and b) -3-(4-methylpyridazinyl) —BrBTD (a and b) -3-(4-methylpyridazinyl) —I BTE (a and b)-3-(4-methylpyridazinyl) -n-butyl BTF (a and b) -3-(4-methylpyridazinyl)-n-propyl BTG (a and b) -3-(4-fluoropyridazinyl) -t-butyl BTH (a and b)-3-(4-fluoropyridazinyl) -iso-butyl BTI (a and b)-3-(4-fluoropyridazinyl) -sec-butyl BTJ (a and b)-3-(4-fluoropyridazinyl) -cyclohexyl BTK (a and b)-3-(4-fluoropyridazinyl) -t-butoxy BTL (a and b)-3-(4-fluoropyridazinyl) -isopropoxy BTM (a and b)-3-(4-fluoropyridazinyl) —CF₃ BTN (a and b) -3-(4-fluoropyridazinyl)—CH₂CF₃ BTO (a and b) -3-(4-fluoropyridazinyl) —OCF₃ BTP (a and b)-3-(4-fluoropyridazinyl) —Cl BTQ (a and b) -3-(4-fluoropyridazinyl) —BrBTR (a and b) -3-(4-fluoropyridazinyl) —I BTS (a and b)-3-(4-fluoropyridazinyl) -n-butyl BTT (a and b) -3-(4-fluoropyridazinyl)-n-propyl BTU (a and b) -5-(4-chlorothiadiazolyl) -t-butyl BTV (a and b)-5-(4-chlorothiadiazolyl) -iso-butyl BTW (a and b)-5-(4-chlorothiadiazolyl) -sec-butyl BTX (a and b)-5-(4-chlorothiadiazolyl) -cyclohexyl BTY (a and b)-5-(4-chlorothiadiazolyl) -t-butoxy BTZ (a and b)-5-(4-chlorothiadiazolyl) -isopropoxy BUA (a and b)-5-(4-chlorothiadiazolyl) —CF₃ BUB (a and b) -5-(4-chlorothiadiazolyl)—CH₂CF₃ BUC (a and b) -5-(4-chlorothiadiazolyl) —OCF₃ BUD (a and b)-5-(4-chlorothiadiazolyl) —Cl BUE (a and b) -5-(4-chlorothiadiazolyl)—Br BUF (a and b) -5-(4-chlorothiadiazolyl) —I BUG (a and b)-5-(4-chlorothiadiazolyl) -n-butyl BUH (a and b)-5-(4-chlorothiadiazolyl) -n-propyl BUI (a and b)-5-(4-methylthiadiazolyl) -t-butyl BUJ (a and b)-5-(4-methylthiadiazolyl) -iso-butyl BUK (a and b)-5-(4-methylthiadiazolyl) -sec-butyl BUL (a and b)-5-(4-methylthiadiazolyl) -cyclohexyl BUM (a and b)-5-(4-methylthiadiazolyl) -t-butoxy BUN (a and b)-5-(4-methylthiadiazolyl) -isopropoxy BUO (a and b)-5-(4-methylthiadiazolyl) —CF₃ BUP (a and b) -5-(4-methylthiadiazolyl)—CH₂CF₃ BUQ (a and b) -5-(4-methylthiadiazolyl) —OCF₃ BUR (a and b)-5-(4-methylthiadiazolyl) —Cl BUS (a and b) -5-(4-methylthiadiazolyl)—Br BUT (a and b) -5-(4-methylthiadiazolyl) —I BUU (a and b)-5-(4-methylthiadiazolyl) -n-butyl BUV (a and b)-5-(4-methylthiadiazolyl) -n-propyl BUW (a and b)-5-(4-fluorothiadiazolyl) -t-butyl BUX (a and b)-5-(4-fluorothiadiazolyl) -iso-butyl BUY (a and b)-5-(4-fluorothiadiazolyl) -sec-butyl BUZ (a and b)-5-(4-fluorothiadiazolyl) -cyclohexyl BVA (a and b)-5-(4-fluorothiadiazolyl) -t-butoxy BVB (a and b)-5-(4-fluorothiadiazolyl) -isopropoxy BVC (a and b)-5-(4-fluorothiadiazolyl) —CF₃ BVD (a and b) -5-(4-fluorothiadiazolyl)—CH₂CF₃ BVE (a and b) -5-(4-fluorothiadiazolyl) —OCF₃ BVF (a and b)-5-(4-fluorothiadiazolyl) —Cl BVG (a and b) -5-(4-fluorothiadiazolyl)—Br BVH (a and b) -5-(4-fluorothiadiazolyl) —I BVI (a and b)-5-(4-fluorothiadiazolyl) -n-butyl BVJ (a and b)-5-(4-fluorothiadiazolyl) -n-propyl

wherein “a” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration and “b” meansthat the carbon of the piperazino group to which the methyl group isattached is in the S configuration

TABLE 5 X

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹BVK (a and b) -2-(3-chloropyridyl) -t-butyl BVL (a and b)-2-(3-chloropyridyl) -iso-butyl BVM (a and b) -2-(3-chloropyridyl)-sec-butyl BVN (a and b) -2-(3-chloropyridyl) -cyclohexyl BVO (a and b)-2-(3-chloropyridyl) -t-butoxy BVP (a and b) -2-(3-chloropyridyl)-isopropoxy BVQ (a and b) -2-(3-chloropyridyl) —CF₃ BVR (a and b)-2-(3-chloropyridyl) —CH₂CF₃ BVS (a and b) -2-(3-chloropyridyl) —OCF₃BVT (a and b) -2-(3-chloropyridyl) —Cl BVU (a and b)-2-(3-chloropyridyl) —Br BVV (a and b) -2-(3-chloropyridyl) —I BVW (aand b) -2-(3-chloropyridyl) -n-butyl BVX (a and b) -2-(3-chloropyridyl)-n-propyl BVY (a and b) -2-(3-fluoropyridyl) -t-butyl BVZ (a and b)-2-(3-fluoropyridyl) -iso-butyl BWA (a and b) -2-(3-fluoropyridyl)-sec-butyl BWB (a and b) -2-(3-fluoropyridyl) -cyclohexyl BWC (a and b)-2-(3-fluoropyridyl) -t-butoxy BWD (a and b) -2-(3-fluoropyridyl)-isopropoxy BWE (a and b) -2-(3-fluoropyridyl) —CF₃ BWF (a and b)-2-(3-fluoropyridyl) —CH₂CF₃ BWG (a and b) -2-(3-fluoropyridyl) —OCF₃BWH (a and b) -2-(3-fluoropyridyl) —Cl BWI (a and b)-2-(3-fluoropyridyl) —Br BWJ (a and b) -2-(3-fluoropyridyl) —I BWK (aand b) -2-(3-fluoropyridyl) -n-butyl BWL (a and b) -2-(3-fluoropyridyl)-n-propyl BWM (a and b) -2-(3-methylpyridyl) -t-butyl BWN (a and b)-2-(3-methylpyridyl) -iso-butyl BWO (a and b) -2-(3-methylpyridyl)-sec-butyl BWP (a and b) -2-(3-methylpyridyl) -cyclohexyl BWQ (a and b)-2-(3-methylpyridyl) -t-butoxy BWR (a and b) -2-(3-methylpyridyl)-isopropoxy BWS (a and b) -2-(3-methylpyridyl) —CF₃ BWT (a and b)-2-(3-methylpyridyl) —CH₂CF₃ BWU (a and b) -2-(3-methylpyridyl) —OCF₃BWV (a and b) -2-(3-methylpyridyl) —Cl BWW (a and b)-2-(3-methylpyridyl) —Br BWX (a and b) -2-(3-methylpyridyl) —I BWY (aand b) -2-(3-methylpyridyl) -n-butyl BWZ (a and b) -2-(3-methylpyridyl)-n-propyl BXA (a and b) -2-(3-CF₃-pyridyl) -t-butyl BXB (a and b)-2-(3-CF₃-pyridyl) -iso-butyl BXC (a and b) -2-(3-CF₃-pyridyl)-sec-butyl BXD (a and b) -2-(3-CF₃-pyridyl) -cyclohexyl BXE (a and b)-2-(3-CF₃-pyridyl) -t-butoxy BXF (a and b) -2-(3-CF₃-pyridyl)-isopropoxy BXG (a and b) -2-(3-CF₃-pyridyl) —CF₃ BXH (a and b)-2-(3-CF₃-pyridyl) —CH₂CF₃ BXI (a and b) -2-(3-CF₃-pyridyl) —OCF₃ BXJ (aand b) -2-(3-CF₃-pyridyl) —Cl BXK (a and b) -2-(3-CF₃-pyridyl) —Br BXL(a and b) -2-(3-CF₃-pyridyl) —I BXM (a and b) -2-(3-CF₃-pyridyl)-n-butyl BXN (a and b) -2-(3-CF₃-pyridyl) -n-propyl BXO (a and b)-2-(3-CHF₂-pyridyl) -t-butyl BXP (a and b) -2-(3-CHF₂-pyridyl)-iso-butyl BXQ (a and b) -2-(3-CHF₂-pyridyl) -sec-butyl BXR (a and b)-2-(3-CHF₂-pyridyl) -cyclohexyl BXS (a and b) -2-(3-CHF₂-pyridyl)-t-butoxy BXT (a and b) -2-(3-CHF₂-pyridyl) -isopropoxy BXU (a and b)-2-(3-CHF₂-pyridyl) —CF₃ BXV (a and b) -2-(3-CHF₂-pyridyl) —CH₂CF₃ BXW(a and b) -2-(3-CHF₂-pyridyl) —OCF₃ BXX (a and b) -2-(3-CHF₂-pyridyl)—Cl BXY (a and b) -2-(3-CHF₂-pyridyl) —Br BXZ (a and b)-2-(3-CHF₂-pyridyl) —I BYA (a and b) -2-(3-CHF₂-pyridyl) -n-butyl BYB (aand b) -2-(3-CHF₂-pyridyl) -n-propyl BYC (a and b) -2-(3-hydroxypyridyl)-t-butyl BYD (a and b) -2-(3-hydroxypyridyl) -iso-butyl BYE (a and b)-2-(3-hydroxypyridyl) -sec-butyl BYF (a and b) -2-(3-hydroxypyridyl)-cyclohexyl BYG (a and b) -2-(3-hydroxypyridyl) -t-butoxy BYH (a and b)-2-(3-hydroxypyridyl) -isopropoxy BYI (a and b) -2-(3-hydroxypyridyl)—CF₃ BYJ (a and b) -2-(3-hydroxypyridyl) —CH₂CF₃ BYK (a and b)-2-(3-hydroxypyridyl) —OCF₃ BYL (a and b) -2-(3-hydroxypyridyl) —Cl BYM(a and b) -2-(3-hydroxypyridyl) —Br BYN (a and b) -2-(3-hydroxypyridyl)—I BYO (a and b) -2-(3-hydroxypyridyl) -n-butyl BYP (a and b)-2-(3-hydroxypyridyl) -n-propyl BYQ (a and b) -2-(3-nitropyridyl)-t-butyl BYR (a and b) -2-(3-nitropyridyl) -iso-butyl BYS (a and b)-2-(3-nitropyridyl) -sec-butyl BYT (a and b) -2-(3-nitropyridyl)-cyclohexyl BYU (a and b) -2-(3-nitropyridyl) -t-butoxy BYV (a and b)-2-(3-nitropyridyl) -isopropoxy BYW (a and b) -2-(3-nitropyridyl) —CF₃BYX (a and b) -2-(3-nitropyridyl) —CH₂CF₃ BYY (a and b)-2-(3-nitropyridyl) —OCF₃ BYZ (a and b) -2-(3-nitropyridyl) —Cl BZA (aand b) -2-(3-nitropyridyl) —Br BZB (a and b) -2-(3-nitropyridyl) —I BZC(a and b) -2-(3-nitropyridyl) -n-butyl BZD (a and b) -2-(3-nitropyridyl)-n-propyl BZE (a and b) -2-(3-cyanopyridyl) -t-butyl BZF (a and b)-2-(3-cyanopyridyl) -iso-butyl BZG (a and b) -2-(3-cyanopyridyl)-sec-butyl BZH (a and b) -2-(3-cyanopyridyl) -cyclohexyl BZI (a and b)-2-(3-cyanopyridyl) -t-butoxy BZJ (a and b) -2-(3-cyanopyridyl)-isopropoxy BZK (a and b) -2-(3-cyanopyridyl) —CF₃ BZL (a and b)-2-(3-cyanopyridyl) —CH₂CF₃ BZM (a and b) -2-(3-cyanopyridyl) —OCF₃ BZN(a and b) -2-(3-cyanopyridyl) —Cl BZO (a and b) -2-(3-cyanopyridyl) —BrBZP (a and b) -2-(3-cyanopyridyl) —I BZQ (a and b) -2-(3-cyanopyridyl)-n-butyl BZR (a and b) -2-(3-cyanopyridyl) -n-propyl BZS (a and b)-2-(3-bromopyridyl) -t-butyl BZT (a and b) -2-(3-bromopyridyl)-iso-butyl BZU (a and b) -2-(3-bromopyridyl) -sec-butyl BZV (a and b)-2-(3-bromopyridyl) -cyclohexyl BZW (a and b) -2-(3-bromopyridyl)-t-butoxy BZX (a and b) -2-(3-bromopyridyl) -isopropoxy BZY (a and b)-2-(3-bromopyridyl) —CF₃ BZZ (a and b) -2-(3-bromopyridyl) —CH₂CF₃ CAA(a and b) -2-(3-bromopyridyl) —OCF₃ CAB (a and b) -2-(3-bromopyridyl)—Cl CAC (a and b) -2-(3-bromopyridyl) —Br CAD (a and b)-2-(3-bromopyridyl) —I CAE (a and b) -2-(3-bromopyridyl) -n-butyl CAF (aand b) -2-(3-bromopyridyl) -n-propyl CAG (a and b) -2-(3-iodopyridyl)-t-butyl CAH (a and b) -2-(3-iodopyridyl) -iso-butyl CAI (a and b)-2-(3-iodopyridyl) -sec-butyl CAJ (a and b) -2-(3-iodopyridyl)-cyclohexyl CAK (a and b) -2-(3-iodopyridyl) -t-butoxy CAL (a and b)-2-(3-iodopyridyl) -isopropoxy CAM (a and b) -2-(3-iodopyridyl) —CF₃ CAN(a and b) -2-(3-iodopyridyl) —CH₂CF₃ CAO (a and b) -2-(3-iodopyridyl)—OCF₃ CAP (a and b) -2-(3-iodopyridyl) —Cl CAQ (a and b)-2-(3-iodopyridyl) —Br CAR (a and b) -2-(3-iodopyridyl) —I CAS (a and b)-2-(3-iodopyridyl) -n-butyl CAT (a and b) -2-(3-iodopyridyl) -n-propylCAU (a and b) -4-(5-chloropyrimidinyl) -t-butyl CAV (a and b)-4-(5-chloropyrimidinyl) -iso-butyl CAW (a and b)-4-(5-chloropyrimidinyl) -sec-butyl CAX (a and b)-4-(5-chloropyrimidinyl) -cyclohexyl CAY (a and b)-4-(5-chloropyrimidinyl) -t-butoxy CAZ (a and b)-4-(5-chloropyrimidinyl) -isopropoxy CBA (a and b)-4-(5-chloropyrimidinyl) —CF₃ CBB (a and b) -4-(5-chloropyrimidinyl)—CH₂CF₃ CBC (a and b) -4-(5-chloropyrimidinyl) —OCF₃ CBD (a and b)-4-(5-chloropyrimidinyl) —Cl CBE (a and b) -4-(5-chloropyrimidinyl) —BrCBF (a and b) -4-(5-chloropyrimidinyl) —I CBG (a and b)-4-(5-chloropyrimidinyl) -n-butyl CBH (a and b) -4-(5-chloropyrimidinyl)-n-propyl CBI (a and b) -4-(5-methylpyrimidinyl) -t-butyl CBJ (a and b)-4-(5-methylpyrimidinyl) -iso-butyl CBK (a and b)-4-(5-methylpyrimidinyl) -sec-butyl CBL (a and b)-4-(5-methylpyrimidinyl) -cyclohexyl CBM (a and b)-4-(5-methylpyrimidinyl) -t-butoxy CBN (a and b)-4-(5-methylpyrimidinyl) -isopropoxy CBO (a and b)-4-(5-methylpyrimidinyl) —CF₃ CBP (a and b) -4-(5-methylpyrimidinyl)—CH₂CF₃ CBQ (a and b) -4-(5-methylpyrimidinyl) —OCF₃ CBR (a and b)-4-(5-methylpyrimidinyl) —Cl CBS (a and b) -4-(5-methylpyrimidinyl) —BrCBT (a and b) -4-(5-methylpyrimidinyl) —I CBU (a and b)-4-(5-methylpyrimidinyl) -n-butyl CBV (a and b) -4-(5-methylpyrimidinyl)-n-propyl CBW (a and b) -4-(5-fluoropyrimidinyl) -t-butyl CBX (a and b)-4-(5-fluoropyrimidinyl) -iso-butyl CBY (a and b)-4-(5-fluoropyrimidinyl) -sec-butyl CBZ (a and b)-4-(5-fluoropyrimidinyl) -cyclohexyl CCA (a and b)-4-(5-fluoropyrimidinyl) -t-butoxy CCB (a and b)-4-(5-fluoropyrimidinyl) -isopropoxy CCC (a and b)-4-(5-fluoropyrimidinyl) —CF₃ CCD (a and b) -4-(5-fluoropyrimidinyl)—CH₂CF₃ CCE (a and b) -4-(5-fluoropyrimidinyl) —OCF₃ CCF (a and b)-4-(5-fluoropyrimidinyl) —Cl CCG (a and b) -4-(5-fluoropyrimidinyl) —BrCCH (a and b) -4-(5-fluoropyrimidinyl) —I CCI (a and b)-4-(5-fluoropyrimidinyl) -n-butyl CCJ (a and b) -4-(5-fluoropyrimidinyl)-n-propyl CCK (a and b) -2-(3-chloropyrazinyl) -t-butyl CCL (a and b)-2-(3-chloropyrazinyl) -iso-butyl CCM (a and b) -2-(3-chloropyrazinyl)-sec-butyl CCN (a and b) -2-(3-chloropyrazinyl) -cyclohexyl CCO (a andb) -2-(3-chloropyrazinyl) -t-butoxy CCP (a and b) -2-(3-chloropyrazinyl)-isopropoxy CCQ (a and b) -2-(3-chloropyrazinyl) —CF₃ CCR (a and b)-2-(3-chloropyrazinyl) —CH₂CF₃ CCS (a and b) -2-(3-chloropyrazinyl)—OCF₃ CCT (a and b) -2-(3-chloropyrazinyl) —Cl CCU (a and b)-2-(3-chloropyrazinyl) —Br CCV (a and b) -2-(3-chloropyrazinyl) —I CCW(a and b) -2-(3-chloropyrazinyl) -n-butyl CCX (a and b)-2-(3-chloropyrazinyl) -n-propyl CCY (a and b) -2-(3-methylpyrazinyl)-t-butyl CCZ (a and b) -2-(3-methylpyrazinyl) -iso-butyl CDA (a and b)-2-(3-methylpyrazinyl) -sec-butyl CDB (a and b) -2-(3-methylpyrazinyl)-cyclohexyl CDC (a and b) -2-(3-methylpyrazinyl) -t-butoxy CDD (a and b)-2-(3-methylpyrazinyl) -isopropoxy CDE (a and b) -2-(3-methylpyrazinyl)—CF₃ CDF (a and b) -2-(3-methylpyrazinyl) —CH₂CF₃ CDG (a and b)-2-(3-methylpyrazinyl) —OCF₃ CDH (a and b) -2-(3-methylpyrazinyl) —ClCDI (a and b) -2-(3-methylpyrazinyl) —Br CDJ (a and b)-2-(3-methylpyrazinyl) —I CDK (a and b) -2-(3-methylpyrazinyl) -n-butylCDL (a and b) -2-(3-methylpyrazinyl) -n-propyl CDM (a and b)-2-(3-fluoropyrazinyl) -t-butyl CDN (a and b) -2-(3-fluoropyrazinyl)-iso-butyl CDO (a and b) -2-(3-fluoropyrazinyl) -sec-butyl CDP (a and b)-2-(3-fluoropyrazinyl) -cyclohexyl CDQ (a and b) -2-(3-fluoropyrazinyl)-t-butoxy CDR (a and b) -2-(3-fluoropyrazinyl) -isopropoxy CDS (a and b)-2-(3-fluoropyrazinyl) —CF₃ CDT (a and b) -2-(3-fluoropyrazinyl) —CH₂CF₃CDU -2-(3-fluoropyrazinyl) —OCF₃ CDV (a and b) -2-(3-fluoropyrazinyl)—Cl CDW (a and b) -2-(3-fluoropyrazinyl) —Br CDX (a and b)-2-(3-fluoropyrazinyl) —I CDY (a and b) -2-(3-fluoropyrazinyl) -n-butylCDZ (a and b) -2-(3-fluoropyrazinyl) -n-propyl CEA (a and b)-3-(4-chloropyridazinyl) -t-butyl CEB (a and b) -3-(4-chloropyridazinyl)-iso-butyl CEC (a and b) -3-(4-chloropyridazinyl) -sec-butyl CED (a andb) -3-(4-chloropyridazinyl) -cyclohexyl CEE (a and b)-3-(4-chloropyridazinyl) -t-butoxy CEF (a and b)-3-(4-chloropyridazinyl) -isopropoxy CEG (a and b)-3-(4-chloropyridazinyl) —CF₃ CEH (a and b) -3-(4-chloropyridazinyl)—CH₂CF₃ CEI (a and b) -3-(4-chloropyridazinyl) —OCF₃ CEJ (a and b)-3-(4-chloropyridazinyl) —Cl CEK (a and b) -3-(4-chloropyridazinyl) —BrCEL (a and b) -3-(4-chloropyridazinyl) —I CEM (a and b)-3-(4-chloropyridazinyl) -n-butyl CEN (a and b) -3-(4-chloropyridazinyl)-n-propyl CEO (a and b) -3-(4-methylpyridazinyl) -t-butyl CEP (a and b)-3-(4-methylpyridazinyl) -iso-butyl CEQ (a and b)-3-(4-methylpyridazinyl) -sec-butyl CER (a and b)-3-(4-methylpyridazinyl) -cyclohexyl CES (a and b)-3-(4-methylpyridazinyl) -t-butoxy CET (a and b)-3-(4-methylpyridazinyl) -isopropoxy CEU (a and b)-3-(4-methylpyridazinyl) —CF₃ CEV (a and b) -3-(4-methylpyridazinyl)—CH₂CF₃ CEW (a and b) -3-(4-methylpyridazinyl) —OCF₃ CEX (a and b)-3-(4-methylpyridazinyl) —Cl CEY (a and b) -3-(4-methylpyridazinyl) —BrCEZ (a and b) -3-(4-methylpyridazinyl) —I CFA (a and b)-3-(4-methylpyridazinyl) -n-butyl CFB (a and b) -3-(4-methylpyridazinyl)-n-propyl CFC (a and b) -3-(4-fluoropyridazinyl) -t-butyl CFD (a and b)-3-(4-fluoropyridazinyl) -iso-butyl CFE (a and b)-3-(4-fluoropyridazinyl) -sec-butyl CFF (a and b)-3-(4-fluoropyridazinyl) -cyclohexyl CFG (a and b)-3-(4-fluoropyridazinyl) -t-butoxy CFH (a and b)-3-(4-fluoropyridazinyl) -isopropoxy CFI (a and b)-3-(4-fluoropyridazinyl) —CF₃ CFJ (a and b) -3-(4-fluoropyridazinyl)—CH₂CF₃ CFK (a and b) -3-(4-fluoropyridazinyl) —OCF₃ CFL (a and b)-3-(4-fluoropyridazinyl) —Cl CFM (a and b) -3-(4-fluoropyridazinyl) —BrCFN (a and b) -3-(4-fluoropyridazinyl) —I CFO (a and b)-3-(4-fluoropyridazinyl) -n-butyl CFP (a and b) -3-(4-fluoropyridazinyl)-n-propyl CFQ (a and b) -5-(4-chlorothiadiazolyl) -t-butyl CFR (a and b)-5-(4-chlorothiadiazolyl) -iso-butyl CFS (a and b)-5-(4-chlorothiadiazolyl) -sec-butyl CFT (a and b)-5-(4-chlorothiadiazolyl) -cyclohexyl CFU (a and b)-5-(4-chlorothiadiazolyl) -t-butoxy CFV (a and b)-5-(4-chlorothiadiazolyl) -isopropoxy CFW (a and b)-5-(4-chlorothiadiazolyl) —CF₃ CFX (a and b) -5-(4-chlorothiadiazolyl)—CH₂CF₃ CFY (a and b) -5-(4-chlorothiadiazolyl) —OCF₃ CFZ (a and b)-5-(4-chlorothiadiazolyl) —Cl CGA (a and b) -5-(4-chlorothiadiazolyl)—Br CGB (a and b) -5-(4-chlorothiadiazolyl) —I CGC (a and b)-5-(4-chlorothiadiazolyl) -n-butyl CGD (a and b)-5-(4-chlorothiadiazolyl) -n-propyl CGE (a and b)-5-(4-methylthiadiazolyl) -t-butyl CGF (a and b)-5-(4-methylthiadiazolyl) -iso-butyl CGG (a and b)-5-(4-methylthiadiazolyl) -sec-butyl CGH (a and b)-5-(4-methylthiadiazolyl) -cyclohexyl CGI (a and b)-5-(4-methylthiadiazolyl) -t-butoxy CGJ (a and b)-5-(4-methylthiadiazolyl) -isopropoxy CGK (a and b)-5-(4-methylthiadiazolyl) —CF₃ CGL (a and b) -5-(4-methylthiadiazolyl)—CH₂CF₃ CGM (a and b) -5-(4-methylthiadiazolyl) —OCF₃ CGN (a and b)-5-(4-methylthiadiazolyl) —Cl CGO (a and b) -5-(4-methylthiadiazolyl)—Br CGP (a and b) -5-(4-methylthiadiazolyl) —I CGQ (a and b)-5-(4-methylthiadiazolyl) -n-butyl CGR (a and b)-5-(4-methylthiadiazolyl) -n-propyl CGS (a and b)-5-(4-fluorothiadiazolyl) -t-butyl CGT (a and b)-5-(4-fluorothiadiazolyl) -iso-butyl CGU (a and b)-5-(4-fluorothiadiazolyl) -sec-butyl CGV (a and b)-5-(4-fluorothiadiazolyl) -cyclohexyl CGW (a and b)-5-(4-fluorothiadiazolyl) -t-butoxy CGX (a and b)-5-(4-fluorothiadiazolyl) -isopropoxy CGY (a and b)-5-(4-fluorothiadiazolyl) —CF₃ CGZ (a and b) -5-(4-fluorothiadiazolyl)—CH₂CF₃ CHA (a and b) -5-(4-fluorothiadiazolyl) —OCF₃ CHB (a and b)-5-(4-fluorothiadiazolyl) —Cl CHC (a and b) -5-(4-fluorothiadiazolyl)—Br CHD (a and b) -5-(4-fluorothiadiazolyl) —I CHE (a and b)-5-(4-fluorothiadiazolyl) -n-butyl CHF (a and b)-5-(4-fluorothiadiazolyl) -n-propyl

wherein “a” means that the carbon atom of the piperazino group to whichthe methyl group is attached is in the R configuration and “b” meansthat the carbon of the piperazino group to which the methyl group isattached is in the S configuration

TABLE 6 XI

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹CHG -2-(3-chloropyridyl) -t-butyl CHH -2-(3-chloropyridyl) -iso-butylCHI -2-(3-chloropyridyl) -sec-butyl CHJ -2-(3-chloropyridyl) -cyclohexylCHK -2-(3-chloropyridyl) -t-butoxy CHL -2-(3-chloropyridyl) -isopropoxyCHM -2-(3-chloropyridyl) —CF₃ CHN -2-(3-chloropyridyl) —CH₂CF₃ CHO-2-(3-chloropyridyl) —OCF₃ CHP -2-(3-chloropyridyl) —Cl CHQ-2-(3-chloropyridyl) —Br CHR -2-(3-chloropyridyl) —I CHS-2-(3-chloropyridyl) -n-butyl CHT -2-(3-chloropyridyl) -n-propyl CHU-2-(3-fluoropyridyl) -t-butyl CHV -2-(3-fluoropyridyl) -iso-butyl CHW-2-(3-fluoropyridyl) -sec-butyl CHX -2-(3-fluoropyridyl) -cyclohexyl CHY-2-(3-fluoropyridyl) -t-butoxy CHZ -2-(3-fluoropyridyl) -isopropoxy CIA-2-(3-fluoropyridyl) —CF₃ CIB -2-(3-fluoropyridyl) —CH₂CF₃ CIC-2-(3-fluoropyridyl) —OCF₃ CID -2-(3-fluoropyridyl) —Cl CIE-2-(3-fluoropyridyl) —Br CIF -2-(3-fluoropyridyl) —I CIG-2-(3-fluoropyridyl) -n-butyl CIH -2-(3-fluoropyridyl) -n-propyl CII-2-(3-methylpyridyl) -t-butyl CIJ -2-(3-methylpyridyl) -iso-butyl CIK-2-(3-methylpyridyl) -sec-butyl CIL -2-(3-methylpyridyl) -cyclohexyl CIM-2-(3-methylpyridyl) -t-butoxy CIN -2-(3-methylpyridyl) -isopropoxy CIO-2-(3-methylpyridyl) —CF₃ CIP -2-(3-methylpyridyl) —CH₂CF₃ CIQ-2-(3-methylpyridyl) —OCF₃ CIR -2-(3-methylpyridyl) —Cl CIS-2-(3-methylpyridyl) —Br CIT -2-(3-methylpyridyl) —I CIU-2-(3-methylpyridyl) -n-butyl CIV -2-(3-methylpyridyl) -n-propyl CIW-2-(3-CF₃-pyridyl) -t-butyl CIX -2-(3-CF₃-pyridyl) -iso-butyl CIY-2-(3-CF₃-pyridyl) -sec-butyl CIZ -2-(3-CF₃-pyridyl) -cyclohexyl CJA-2-(3-CF₃-pyridyl) -t-butoxy CJB -2-(3-CF₃-pyridyl) -isopropoxy CJC-2-(3-CF₃-pyridyl) —CF₃ CJD -2-(3-CF₃-pyridyl) —CH₂CF₃ CJE-2-(3-CF₃-pyridyl) —OCF₃ CJF -2-(3-CF₃-pyridyl) —Cl CJG-2-(3-CF₃-pyridyl) —Br CJH -2-(3-CF₃-pyridyl) —I CJI -2-(3-CF₃-pyridyl)-n-butyl CJJ -2-(3-CF₃-pyridyl) -n-propyl CJK -2-(3-CHF₂-pyridyl)-t-butyl CJL -2-(3-CHF₂-pyridyl) -iso-butyl CJM -2-(3-CHF₂-pyridyl)-sec-butyl CIN -2-(3-CHF₂-pyridyl) -cyclohexyl CJO -2-(3-CHF₂-pyridyl)-t-butoxy CJP -2-(3-CHF₂-pyridyl) -isopropoxy CJQ -2-(3-CHF₂-pyridyl)—CF₃ CJR -2-(3-CHF₂-pyridyl) —CH₂CF₃ CJS -2-(3-CHF₂-pyridyl) —OCF₃ CJT-2-(3-CHF₂-pyridyl) —Cl CJU -2-(3-CHF₂-pyridyl) —Br CJV-2-(3-CHF₂-pyridyl) —I CJW -2-(3-CHF₂-pyridyl) -n-butyl CJX-2-(3-CHF₂-pyridyl) -n-propyl CJY -2-(3-hydroxypyridyl) -t-butyl CJZ-2-(3-hydroxypyridyl) -iso-butyl CKA -2-(3-hydroxypyridyl) -sec-butylCKB -2-(3-hydroxypyridyl) -cyclohexyl CKC -2-(3-hydroxypyridyl)-t-butoxy CKD -2-(3-hydroxypyridyl) -isopropoxy CKE-2-(3-hydroxypyridyl) —CF₃ CKF -2-(3-hydroxypyridyl) —CH₂CF₃ CKG-2-(3-hydroxypyridyl) —OCF₃ CKH -2-(3-hydroxypyridyl) —Cl CKI-2-(3-hydroxypyridyl) —Br CKJ -2-(3-hydroxypyridyl) —I CKK-2-(3-hydroxypyridyl) -n-butyl CKL -2-(3-hydroxypyridyl) -n-propyl CKM-2-(3-nitropyridyl) -t-butyl CKN -2-(3-nitropyridyl) -iso-butyl CKO-2-(3-nitropyridyl) -sec-butyl CKP -2-(3-nitropyridyl) -cyclohexyl CKQ-2-(3-nitropyridyl) -t-butoxy CKR -2-(3-nitropyridyl) -isopropoxy CKS-2-(3-nitropyridyl) —CF₃ CKT -2-(3-nitropyridyl) —CH₂CF₃ CKU-2-(3-nitropyridyl) —OCF₃ CKV -2-(3-nitropyridyl) —Cl CKW-2-(3-nitropyridyl) —Br CKX -2-(3-nitropyridyl) —I CKY-2-(3-nitropyridyl) -n-butyl CKZ -2-(3-nitropyridyl) -n-propyl CLA-2-(3-cyanopyridyl) -t-butyl CLB -2-(3-cyanopyridyl) -iso-butyl CLC-2-(3-cyanopyridyl) -sec-butyl CLD -2-(3-cyanopyridyl) -cyclohexyl CLE-2-(3-cyanopyridyl) -t-butoxy CLF -2-(3-cyanopyridyl) -isopropoxy CLG-2-(3-cyanopyridyl) —CF₃ CLH -2-(3-cyanopyridyl) —CH₂CF₃ CLI-2-(3-cyanopyridyl) —OCF₃ CLJ -2-(3-cyanopyridyl) —Cl CLK-2-(3-cyanopyridyl) —Br CLL -2-(3-cyanopyridyl) —I CLM-2-(3-cyanopyridyl) -n-butyl CLN -2-(3-cyanopyridyl) -n-propyl CLO-2-(3-bromopyridyl) -t-butyl CLP -2-(3-bromopyridyl) -iso-butyl CLQ-2-(3-bromopyridyl) -sec-butyl CLR -2-(3-bromopyridyl) -cyclohexyl CLS-2-(3-bromopyridyl) -t-butoxy CLT -2-(3-bromopyridyl) -isopropoxy CLU-2-(3-bromopyridyl) —CF₃ CLV -2-(3-bromopyridyl) —CH₂CF₃ CLW-2-(3-bromopyridyl) —OCF₃ CLX -2-(3-bromopyridyl) —Cl CLY-2-(3-bromopyridyl) —Br CLZ -2-(3-bromopyridyl) —I CMA-2-(3-bromopyridyl) -n-butyl CMB -2-(3-bromopyridyl) -n-propyl CMC-2-(3-iodopyridyl) -t-butyl CMD -2-(3-iodopyridyl) -iso-butyl CME-2-(3-iodopyridyl) -sec-butyl CMF -2-(3-iodopyridyl) -cyclohexyl CMG-2-(3-iodopyridyl) -t-butoxy CMH -2-(3-iodopyridyl) -isopropoxy CMI-2-(3-iodopyridyl) —CF₃ CMJ -2-(3-iodopyridyl) —CH₂CF₃ CMK-2-(3-iodopyridyl) —OCF₃ CML -2-(3-iodopyridyl) —Cl CMM-2-(3-iodopyridyl) —Br CMN -2-(3-iodopyridyl) —I CMO -2-(3-iodopyridyl)-n-butyl CMP -2-(3-iodopyridyl) -n-propyl CMQ -4-(5-chloropyrimidinyl)-t-butyl CMR -4-(5-chloropyrimidinyl) -iso-butyl CMS-4-(5-chloropyrimidinyl) -sec-butyl CMT -4-(5-chloropyrimidinyl)-cyclohexyl CMU -4-(5-chloropyrimidinyl) -t-butoxy CMV-4-(5-chloropyrimidinyl) -isopropoxy CMW -4-(5-chloropyrimidinyl) —CF₃CMX -4-(5-chloropyrimidinyl) —CH₂CF₃ CMY -4-(5-chloropyrimidinyl) —OCF₃CMZ -4-(5-chloropyrimidinyl) —Cl CNA -4-(5-chloropyrimidinyl) —Br CNB-4-(5-chloropyrimidinyl) —I CNC -4-(5-chloropyrimidinyl) -n-butyl CND-4-(5-chloropyrimidinyl) -n-propyl CNE -4-(5-methylpyrimidinyl) -t-butylCNF -4-(5-methylpyrimidinyl) -iso-butyl CNG -4-(5-methylpyrimidinyl)-sec-butyl CNH -4-(5-methylpyrimidinyl) -cyclohexyl CNI-4-(5-methylpyrimidinyl) -t-butoxy CNJ -4-(5-methylpyrimidinyl)-isopropoxy CNK -4-(5-methylpyrimidinyl) —CF₃ CNL-4-(5-methylpyrimidinyl) —CH₂CF₃ CNM -4-(5-methylpyrimidinyl) —OCF₃ CNN-4-(5-methylpyrimidinyl) —Cl CNO -4-(5-methylpyrimidinyl) —Br CNP-4-(5-methylpyrimidinyl) —I CNQ -4-(5-methylpyrimidinyl) -n-butyl CNR-4-(5-methylpyrimidinyl) -n-propyl CNS -4-(5-fluoropyrimidinyl) -t-butylCNT -4-(5-fluoropyrimidinyl) -iso-butyl CNU -4-(5-fluoropyrimidinyl)-sec-butyl CNV -4-(5-fluoropyrimidinyl) -cyclohexyl CNW-4-(5-fluoropyrimidinyl) -t-butoxy CNX -4-(5-fluoropyrimidinyl)-isopropoxy CNY -4-(5-fluoropyrimidinyl) —CF₃ CNZ-4-(5-fluoropyrimidinyl) —CH₂CF₃ COA -4-(5-fluoropyrimidinyl) —OCF₃ COB-4-(5-fluoropyrimidinyl) —Cl COC -4-(5-fluoropyrimidinyl) —Br COD-4-(5-fluoropyrimidinyl) —I COE -4-(5-fluoropyrimidinyl) -n-butyl COF-4-(5-fluoropyrimidinyl) -n-propyl COG -2-(3-chloropyrazinyl) -t-butylCOH -2-(3-chloropyrazinyl) -iso-butyl COI -2-(3-chloropyrazinyl)-sec-butyl COJ -2-(3-chloropyrazinyl) -cyclohexyl COK-2-(3-chloropyrazinyl) -t-butoxy COL -2-(3-chloropyrazinyl) -isopropoxyCOM -2-(3-chloropyrazinyl) —CF₃ CON -2-(3-chloropyrazinyl) —CH₂CF₃ COO-2-(3-chloropyrazinyl) —OCF₃ COP -2-(3-chloropyrazinyl) —Cl COQ-2-(3-chloropyrazinyl) —Br COR -2-(3-chloropyrazinyl) —I COS-2-(3-chloropyrazinyl) -n-butyl COT -2-(3-chloropyrazinyl) -n-propyl COU-2-(3-methylpyrazinyl) -t-butyl COV -2-(3-methylpyrazinyl) -iso-butylCOW -2-(3-methylpyrazinyl) -sec-butyl COX -2-(3-methylpyrazinyl)-cyclohexyl COY -2-(3-methylpyrazinyl) -t-butoxy COZ-2-(3-methylpyrazinyl) -isopropoxy CPA -2-(3-methylpyrazinyl) —CF₃ CPB-2-(3-methylpyrazinyl) —CH₂CF₃ CPC -2-(3-methylpyrazinyl) —OCF₃ CPD-2-(3-methylpyrazinyl) —Cl CPE -2-(3-methylpyrazinyl) —Br CPF-2-(3-methylpyrazinyl) —I CPG -2-(3-methylpyrazinyl) -n-butyl CPH-2-(3-methylpyrazinyl) -n-propyl CPI -2-(3-fluoropyrazinyl) -t-butyl CPJ-2-(3-fluoropyrazinyl) -iso-butyl CPK -2-(3-fluoropyrazinyl) -sec-butylCPL -2-(3-fluoropyrazinyl) -cyclohexyl CPM -2-(3-fluoropyrazinyl)-t-butoxy CPN -2-(3-fluoropyrazinyl) -isopropoxy CPO-2-(3-fluoropyrazinyl) —CF₃ CPP -2-(3-fluoropyrazinyl) —CH₂CF₃ CPQ-2-(3-fluoropyrazinyl) —OCF₃ CPR -2-(3-fluoropyrazinyl) —Cl CPS-2-(3-fluoropyrazinyl) —Br CPT -2-(3-fluoropyrazinyl) —I CPU-2-(3-fluoropyrazinyl) -n-butyl CPV -2-(3-fluoropyrazinyl) -n-propyl CPW-3-(4-chloropyridazinyl) -t-butyl CPX -3-(4-chloropyridazinyl)-iso-butyl CPY -3-(4-chloropyridazinyl) -sec-butyl CPZ-3-(4-chloropyridazinyl) -cyclohexyl CQA -3-(4-chloropyridazinyl)-t-butoxy CQB -3-(4-chloropyridazinyl) -isopropoxy CQC-3-(4-chloropyridazinyl) —CF₃ CQD -3-(4-chloropyridazinyl) —CH₂CF₃ CQE-3-(4-chloropyridazinyl) —OCF₃ CQF -3-(4-chloropyridazinyl) —Cl CQG-3-(4-chloropyridazinyl) —Br CQH -3-(4-chloropyridazinyl) —I CQI-3-(4-chloropyridazinyl) -n-butyl CQJ -3-(4-chloropyridazinyl) -n-propylCQK -3-(4-methylpyridazinyl) -t-butyl CQL -3-(4-methylpyridazinyl)-iso-butyl CQM -3-(4-methylpyridazinyl) -sec-butyl CQN-3-(4-methylpyridazinyl) -cyclohexyl CQO -3-(4-methylpyridazinyl)-t-butoxy CQP -3-(4-methylpyridazinyl) -isopropoxy CQQ-3-(4-methylpyridazinyl) —CF₃ CQR -3-(4-methylpyridazinyl) —CH₂CF₃ CQS-3-(4-methylpyridazinyl) —OCF₃ CQT -3-(4-methylpyridazinyl) —Cl CQU-3-(4-methylpyridazinyl) —Br CQV -3-(4-methylpyridazinyl) —I CQW-3-(4-methylpyridazinyl) -n-butyl CQX -3-(4-methylpyridazinyl) -n-propylCQY -3-(4-fluoropyridazinyl) -t-butyl CQZ -3-(4-fluoropyridazinyl)-iso-butyl CRA -3-(4-fluoropyridazinyl) -sec-butyl CRB-3-(4-fluoropyridazinyl) -cyclohexyl CRC -3-(4-fluoropyridazinyl)-t-butoxy CRD -3-(4-fluoropyridazinyl) -isopropoxy CRE-3-(4-fluoropyridazinyl) —CF₃ CRF -3-(4-fluoropyridazinyl) —CH₂CF₃ CRG-3-(4-fluoropyridazinyl) —OCF₃ CRH -3-(4-fluoropyridazinyl) —Cl CRI-3-(4-fluoropyridazinyl) —Br CRJ -3-(4-fluoropyridazinyl) —I CRK-3-(4-fluoropyridazinyl) -n-butyl CRL -3-(4-fluoropyridazinyl) -n-propylCRM -5-(4-chlorothiadiazolyl) -t-butyl CRN -5-(4-chlorothiadiazolyl)-iso-butyl CRO -5-(4-chlorothiadiazolyl) -sec-butyl CRP-5-(4-chlorothiadiazolyl) -cyclohexyl CRQ -5-(4-chlorothiadiazolyl)-t-butoxy CRR -5-(4-chlorothiadiazolyl) -isopropoxy CRS-5-(4-chlorothiadiazolyl) —CF₃ CRT -5-(4-chlorothiadiazolyl) —CH₂CF₃ CRU-5-(4-chlorothiadiazolyl) —OCF₃ CRV -5-(4-chlorothiadiazolyl) —Cl CRW-5-(4-chlorothiadiazolyl) —Br CRX -5-(4-chlorothiadiazolyl) —I CRY-5-(4-chlorothiadiazolyl) -n-butyl CRZ -5-(4-chlorothiadiazolyl)-n-propyl CSA -5-(4-methylthiadiazolyl) -t-butyl CSB-5-(4-methylthiadiazolyl) -iso-butyl CSC -5-(4-methylthiadiazolyl)-sec-butyl CSD -5-(4-methylthiadiazolyl) -cyclohexyl CSE-5-(4-methylthiadiazolyl) -t-butoxy CSF -5-(4-methylthiadiazolyl)-isopropoxy CSG -5-(4-methylthiadiazolyl) —CF₃ CSH-5-(4-methylthiadiazolyl) —CH₂CF₃ CSI -5-(4-methylthiadiazolyl) —OCF₃CSJ -5-(4-methylthiadiazolyl) —Cl CSK -5-(4-methylthiadiazolyl) —Br CSL-5-(4-methylthiadiazolyl) —I CSM -5-(4-methylthiadiazolyl) -n-butyl CSN-5-(4-methylthiadiazolyl) -n-propyl CSO -5-(4-fluorothiadiazolyl)-t-butyl CSP -5-(4-fluorothiadiazolyl) -iso-butyl CSQ-5-(4-fluorothiadiazolyl) -sec-butyl CSR -5-(4-fluorothiadiazolyl)-cyclohexyl CSS -5-(4-fluorothiadiazolyl) -t-butoxy CST-5-(4-fluorothiadiazolyl) -isopropoxy CSU -5-(4-fluorothiadiazolyl) —CF₃CSV -5-(4-fluorothiadiazolyl) —CH₂CF₃ CSW -5-(4-fluorothiadiazolyl)—OCF₃ CSX -5-(4-fluorothiadiazolyl) —Cl CSY -5-(4-fluorothiadiazolyl)—Br CSZ -5-(4-fluorothiadiazolyl) —I CTA -5-(4-fluorothiadiazolyl)-n-butyl CTB -5-(4-fluorothiadiazolyl) -n-propyl

TABLE 7

and pharmaceutically acceptable salts thereof, wherein: Compound Ar R⁹CTC -2-(3-chloropyridyl) -t-butyl CTD -2-(3-chloropyridyl) -iso-butylCTE -2-(3-chloropyridyl) -sec-butyl CTF -2-(3-chloropyridyl) -cyclohexylCTG -2-(3-chloropyridyl) -t-butoxy CTH -2-(3-chloropyridyl) -isopropoxyCTI -2-(3-chloropyridyl) —CF₃ CTJ -2-(3-chloropyridyl) —CH₂CF₃ CTK-2-(3-chloropyridyl) —OCF₃ CTL -2-(3-chloropyridyl) —Cl CTM-2-(3-chloropyridyl) —Br CTN -2-(3-chloropyridyl) —I CTO-2-(3-chloropyridyl) -n-butyl CTP -2-(3-chloropyridyl) -n-propyl CTQ-2-(3-fluoropyridyl) -t-butyl CTR -2-(3-fluoropyridyl) -iso-butyl CTS-2-(3-fluoropyridyl) -sec-butyl CTT -2-(3-fluoropyridyl) -cyclohexyl CTU-2-(3-fluoropyridyl) -t-butoxy CTV -2-(3-fluoropyridyl) -isopropoxy CTW-2-(3-fluoropyridyl) —CF₃ CTX -2-(3-fluoropyridyl) —CH₂CF₃ CTY-2-(3-fluoropyridyl) —OCF₃ CTZ -2-(3-fluoropyridyl) —Cl CUA-2-(3-fluoropyridyl) —Br CUB -2-(3-fluoropyridyl) —I CUC-2-(3-fluoropyridyl) -n-butyl CUD -2-(3-fluoropyridyl) -n-propyl CUE-2-(3-methylpyridyl) -t-butyl CUF -2-(3-methylpyridyl) -iso-butyl CUG-2-(3-methylpyridyl) -sec-butyl CUH -2-(3-methylpyridyl) -cyclohexyl CUI-2-(3-methylpyridyl) -t-butoxy CUJ -2-(3-methylpyridyl) -isopropoxy CUK-2-(3-methylpyridyl) —CF₃ CUL -2-(3-methylpyridyl) —CH₂CF₃ CUM-2-(3-methylpyridyl) —OCF₃ CUN -2-(3-methylpyridyl) —Cl CUO-2-(3-methylpyridyl) —Br CUP -2-(3-methylpyridyl) —I CUQ-2-(3-methylpyridyl) -n-butyl CUR -2-(3-methylpyridyl) -n-propyl CUS-2-(3-CF₃-pyridyl) -t-butyl CUT -2-(3-CF₃-pyridyl) -iso-butyl CUU-2-(3-CF₃-pyridyl) -sec-butyl CUV -2-(3-CF₃-pyridyl) -cyclohexyl CUW-2-(3-CF₃-pyridyl) -t-butoxy CUX -2-(3-CF₃-pyridyl) -isopropoxy CUY-2-(3-CF₃-pyridyl) —CF₃ CUZ -2-(3-CF₃-pyridyl) —CH₂CF₃ CVA-2-(3-CF₃-pyridyl) —OCF₃ CVB -2-(3-CF₃-pyridyl) —Cl CVC-2-(3-CF₃-pyridyl) —Br CVD -2-(3-CF₃-pyridyl) —I CVE -2-(3-CF₃-pyridyl)-n-butyl CVF -2-(3-CF₃-pyridyl) -n-propyl CVG -2-(3-CHF₂-pyridyl)-t-butyl CVH -2-(3-CHF₂-pyridyl) -iso-butyl CVI -2-(3-CHF₂-pyridyl)-sec-butyl CVJ -2-(3-CHF₂-pyridyl) -cyclohexyl CVK -2-(3-CHF₂-pyridyl)-t-butoxy CVL -2-(3-CHF₂-pyridyl) -isopropoxy CVM -2-(3-CHF₂-pyridyl)—CF₃ CVN -2-(3-CHF₂-pyridyl) —CH₂CF₃ CVO -2-(3-CHF₂-pyridyl) —OCF₃ CVP-2-(3-CHF₂-pyridyl) —Cl CVQ -2-(3-CHF₂-pyridyl) —Br CVR-2-(3-CHF₂-pyridyl) —I CVS -2-(3-CHF₂-pyridyl) -n-butyl CVT-2-(3-CHF₂-pyridyl) -n-propyl CVU -2-(3-hydroxypyridyl) -t-butyl CVV-2-(3-hydroxypyridyl) -iso-butyl CVW -2-(3-hydroxypyridyl) -sec-butylCVX -2-(3-hydroxypyridyl) -cyclohexyl CVY -2-(3-hydroxypyridyl)-t-butoxy CVZ -2-(3-hydroxypyridyl) -isopropoxy CWA-2-(3-hydroxypyridyl) —CF₃ CWB -2-(3-hydroxypyridyl) —CH₂CF₃ CWC-2-(3-hydroxypyridyl) —OCF₃ CWD -2-(3-hydroxypyridyl) —Cl CWE-2-(3-hydroxypyridyl) —Br CWF -2-(3-hydroxypyridyl) —I CWG-2-(3-hydroxypyridyl) -n-butyl CWH -2-(3-hydroxypyridyl) -n-propyl CWI-2-(3-nitropyridyl) -t-butyl CWJ -2-(3-nitropyridyl) -iso-butyl CWK-2-(3-nitropyridyl) -sec-butyl CWL -2-(3-nitropyridyl) -cyclohexyl CWM-2-(3-nitropyridyl) -t-butoxy CWN -2-(3-nitropyridyl) -isopropoxy CWO-2-(3-nitropyridyl) —CF₃ CWP -2-(3-nitropyridyl) —CH₂CF₃ CWQ-2-(3-nitropyridyl) —OCF₃ CWR -2-(3-nitropyridyl) —Cl CWS-2-(3-nitropyridyl) —Br CWT -2-(3-nitropyridyl) —I CWU-2-(3-nitropyridyl) -n-butyl CWV -2-(3-nitropyridyl) -n-propyl CWW-2-(3-cyanopyridyl) -t-butyl CWX -2-(3-cyanopyridyl) -iso-butyl CWY-2-(3-cyanopyridyl) -sec-butyl CWZ -2-(3-cyanopyridyl) -cyclohexyl CXA-2-(3-cyanopyridyl) -t-butoxy CXB -2-(3-cyanopyridyl) -isopropoxy CXC-2-(3-cyanopyridyl) —CF₃ CXD -2-(3-cyanopyridyl) —CH₂CF₃ CXE-2-(3-cyanopyridyl) —OCF₃ CXF -2-(3-cyanopyridyl) —Cl CXG-2-(3-cyanopyridyl) —Br CXH -2-(3-cyanopyridyl) —I CXI-2-(3-cyanopyridyl) -n-butyl CXJ -2-(3-cyanopyridyl) -n-propyl CXK-2-(3-bromopyridyl) -t-butyl CXL -2-(3-bromopyridyl) -iso-butyl CXM-2-(3-bromopyridyl) -sec-butyl CXN -2-(3-bromopyridyl) -cyclohexyl CXO-2-(3-bromopyridyl) -t-butoxy CXP -2-(3-bromopyridyl) -isopropoxy CXQ-2-(3-bromopyridyl) —CF₃ CXR -2-(3-bromopyridyl) —CH₂CF₃ CXS-2-(3-bromopyridyl) —OCF₃ CXT -2-(3-bromopyridyl) —Cl CXU-2-(3-bromopyridyl) —Br CXV -2-(3-bromopyridyl) —I CXW-2-(3-bromopyridyl) -n-butyl CXX -2-(3-bromopyridyl) -n-propyl CXY-2-(3-iodopyridyl) -t-butyl CXZ -2-(3-iodopyridyl) -iso-butyl CYA-2-(3-iodopyridyl) -sec-butyl CYB -2-(3-iodopyridyl) -cyclohexyl CYC-2-(3-iodopyridyl) -t-butoxy CYD -2-(3-iodopyridyl) -isopropoxy CYE-2-(3-iodopyridyl) —CF₃ CYF -2-(3-iodopyridyl) —CH₂CF₃ CYG-2-(3-iodopyridyl) —OCF₃ CYH -2-(3-iodopyridyl) —Cl CYI-2-(3-iodopyridyl) —Br CYJ -2-(3-iodopyridyl) —I CYK -2-(3-iodopyridyl)-n-butyl CYL -2-(3-iodopyridyl) -n-propyl CYM -4-(5-chloropyrimidinyl)-t-butyl CYN -4-(5-chloropyrimidinyl) -iso-butyl CYO-4-(5-chloropyrimidinyl) -sec-butyl CYP -4-(5-chloropyrimidinyl)-cyclohexyl CYQ -4-(5-chloropyrimidinyl) -t-butoxy CYR-4-(5-chloropyrimidinyl) -isopropoxy CYS -4-(5-chloropyrimidinyl) —CF₃CYT -4-(5-chloropyrimidinyl) —CH₂CF₃ CYU -4-(5-chloropyrimidinyl) —OCF₃CYV -4-(5-chloropyrimidinyl) —Cl CYW -4-(5-chloropyrimidinyl) —Br CYX-4-(5-chloropyrimidinyl) —I CYY -4-(5-chloropyrimidinyl) -n-butyl CYZ-4-(5-chloropyrimidinyl) -n-propyl CZA -4-(5-methylpyrimidinyl) -t-butylCZB -4-(5-methylpyrimidinyl) -iso-butyl CZC -4-(5-methylpyrimidinyl)-sec-butyl CZD -4-(5-methylpyrimidinyl) -cyclohexyl CZE-4-(5-methylpyrimidinyl) -t-butoxy CZF -4-(5-methylpyrimidinyl)-isopropoxy CZG -4-(5-methylpyrimidinyl) —CF₃ CZH-4-(5-methylpyrimidinyl) —CH₂CF₃ CZI -4-(5-methylpyrimidinyl) —OCF₃ CZJ-4-(5-methylpyrimidinyl) —Cl CZK -4-(5-methylpyrimidinyl) —Br CZL-4-(5-methylpyrimidinyl) —I CZM -4-(5-methylpyrimidinyl) -n-butyl CZN-4-(5-methylpyrimidinyl) -n-propyl CZO -4-(5-fluoropyrimidinyl) -t-butylCZP -4-(5-fluoropyrimidinyl) -iso-butyl CZQ -4-(5-fluoropyrimidinyl)-sec-butyl CZR -4-(5-fluoropyrimidinyl) -cyclohexyl CZS-4-(5-fluoropyrimidinyl) -t-butoxy CZT -4-(5-fluoropyrimidinyl)-isopropoxy CZU -4-(5-fluoropyrimidinyl) —CF₃ CZV-4-(5-fluoropyrimidinyl) —CH₂CF₃ CZW -4-(5-fluoropyrimidinyl) —OCF₃ CZX-4-(5-fluoropyrimidinyl) —Cl CZY -4-(5-fluoropyrimidinyl) —Br CZZ-4-(5-fluoropyrimidinyl) —I DAA -4-(5-fluoropyrimidinyl) -n-butyl DAB-4-(5-fluoropyrimidinyl) -n-propyl DAC -2-(3-chloropyrazinyl) -t-butylDAD -2-(3-chloropyrazinyl) -iso-butyl DAE -2-(3-chloropyrazinyl)-sec-butyl DAF -2-(3-chloropyrazinyl) -cyclohexyl DAG-2-(3-chloropyrazinyl) -t-butoxy DAH -2-(3-chloropyrazinyl) -isopropoxyDAI -2-(3-chloropyrazinyl) —CF₃ DAJ -2-(3-chloropyrazinyl) —CH₂CF₃ DAK-2-(3-chloropyrazinyl) —OCF₃ DAL -2-(3-chloropyrazinyl) —Cl DAM-2-(3-chloropyrazinyl) —Br DAN -2-(3-chloropyrazinyl) —I DAO-2-(3-chloropyrazinyl) -n-butyl DAP -2-(3-chloropyrazinyl) -n-propyl DAQ-2-(3-methylpyrazinyl) -t-butyl DAR -2-(3-methylpyrazinyl) -iso-butylDAS -2-(3-methylpyrazinyl) -sec-butyl DAT -2-(3-methylpyrazinyl)-cyclohexyl DAU -2-(3-methylpyrazinyl) -t-butoxy DAV-2-(3-methylpyrazinyl) -isopropoxy DAW -2-(3-methylpyrazinyl) —CF₃ DAX-2-(3-methylpyrazinyl) —CH₂CF₃ DAY -2-(3-methylpyrazinyl) —OCF₃ DAZ-2-(3-methylpyrazinyl) —Cl DBA -2-(3-methylpyrazinyl) —Br DBB-2-(3-methylpyrazinyl) —I DBC -2-(3-methylpyrazinyl) -n-butyl DBD-2-(3-methylpyrazinyl) -n-propyl DBE -2-(3-fluoropyrazinyl) -t-butyl DBF-2-(3-fluoropyrazinyl) -iso-butyl DBG -2-(3-fluoropyrazinyl) -sec-butylDBH -2-(3-fluoropyrazinyl) -cyclohexyl DBI -2-(3-fluoropyrazinyl)-t-butoxy DBJ -2-(3-fluoropyrazinyl) -isopropoxy DBK-2-(3-fluoropyrazinyl) —CF₃ DBL -2-(3-fluoropyrazinyl) —CH₂CF₃ DBM-2-(3-fluoropyrazinyl) —OCF₃ DBN -2-(3-fluoropyrazinyl) —Cl DBO-2-(3-fluoropyrazinyl) —Br DBP -2-(3-fluoropyrazinyl) —I DBQ-2-(3-fluoropyrazinyl) -n-butyl DBR -2-(3-fluoropyrazinyl) -n-propyl DBS-3-(4-chloropyridazinyl) -t-butyl DBT -3-(4-chloropyridazinyl)-iso-butyl DBU -3-(4-chloropyridazinyl) -sec-butyl DBV-3-(4-chloropyridazinyl) -cyclohexyl DBW -3-(4-chloropyridazinyl)-t-butoxy DBX -3-(4-chloropyridazinyl) -isopropoxy DBY-3-(4-chloropyridazinyl) —CF₃ DBZ -3-(4-chloropyridazinyl) —CH₂CF₃ DCA-3-(4-chloropyridazinyl) —OCF₃ DCB -3-(4-chloropyridazinyl) —Cl DCC-3-(4-chloropyridazinyl) —Br DCD -3-(4-chloropyridazinyl) —I DCE-3-(4-chloropyridazinyl) -n-butyl DCF -3-(4-chloropyridazinyl) -n-propylDCG -3-(4-methylpyridazinyl) -t-butyl DCH -3-(4-methylpyridazinyl)-iso-butyl DCI -3-(4-methylpyridazinyl) -sec-butyl DCJ-3-(4-methylpyridazinyl) -cyclohexyl DCK -3-(4-methylpyridazinyl)-t-butoxy DCL -3-(4-methylpyridazinyl) -isopropoxy DCM-3-(4-methylpyridazinyl) —CF₃ DCN -3-(4-methylpyridazinyl) —CH₂CF₃ DCO-3-(4-methylpyridazinyl) —OCF₃ DCP -3-(4-methylpyridazinyl) —Cl DCQ-3-(4-methylpyridazinyl) —Br DCR -3-(4-methylpyridazinyl) —I DCS-3-(4-methylpyridazinyl) -n-butyl DCT -3-(4-methylpyridazinyl) -n-propylDCU -3-(4-fluoropyridazinyl) -t-butyl DCV -3-(4-fluoropyridazinyl)-iso-butyl DCW -3-(4-fluoropyridazinyl) -sec-butyl DCX-3-(4-fluoropyridazinyl) -cyclohexyl DCY -3-(4-fluoropyridazinyl)-t-butoxy DCZ -3-(4-fluoropyridazinyl) -isopropoxy DDA-3-(4-fluoropyridazinyl) —CF₃ DDB -3-(4-fluoropyridazinyl) —CH₂CF₃ DDC-3-(4-fluoropyridazinyl) —OCF₃ DDD -3-(4-fluoropyridazinyl) —Cl DDE-3-(4-fluoropyridazinyl) —Br DDF -3-(4-fluoropyridazinyl) —I DDG-3-(4-fluoropyridazinyl) -n-butyl DDH -3-(4-fluoropyridazinyl) -n-propylDDI -5-(4-chlorothiadiazolyl) -t-butyl DDJ -5-(4-chlorothiadiazolyl)-iso-butyl DDK -5-(4-chlorothiadiazolyl) -sec-butyl DDL-5-(4-chlorothiadiazolyl) -cyclohexyl DDM -5-(4-chlorothiadiazolyl)-t-butoxy DDN -5-(4-chlorothiadiazolyl) -isopropoxy DDO-5-(4-chlorothiadiazolyl) —CF₃ DDP -5-(4-chlorothiadiazolyl) —CH₂CF₃ DDQ-5-(4-chlorothiadiazolyl) —OCF₃ DDR -5-(4-chlorothiadiazolyl) —Cl DDS-5-(4-chlorothiadiazolyl) —Br DDT -5-(4-chlorothiadiazolyl) —I DDU-5-(4-chlorothiadiazolyl) -n-butyl DDV -5-(4-chlorothiadiazolyl)-n-propyl DDW -5-(4-methylthiadiazolyl) -t-butyl DDX-5-(4-methylthiadiazolyl) -iso-butyl DDY -5-(4-methylthiadiazolyl)-sec-butyl DDZ -5-(4-methylthiadiazolyl) -cyclohexyl DEA-5-(4-methylthiadiazolyl) -t-butoxy DEB -5-(4-methylthiadiazolyl)-isopropoxy DEC -5-(4-methylthiadiazolyl) —CF₃ DED-5-(4-methylthiadiazolyl) —CH₂CF₃ DEE -5-(4-methylthiadiazolyl) —OCF₃DEF -5-(4-methylthiadiazolyl) —Cl DEG -5-(4-methylthiadiazolyl) —Br DEH-5-(4-methylthiadiazolyl) —I DEI -5-(4-methylthiadiazolyl) -n-butyl DEJ-5-(4-methylthiadiazolyl) -n-propyl DEK -5-(4-fluorothiadiazolyl)-t-butyl DEL -5-(4-fluorothiadiazolyl) -iso-butyl DEM-5-(4-fluorothiadiazolyl) -sec-butyl DEN -5-(4-fluorothiadiazolyl)-cyclohexyl DEO -5-(4-fluorothiadiazolyl) -t-butoxy DEP-5-(4-fluorothiadiazolyl) -isopropoxy DEQ -5-(4-fluorothiadiazolyl) —CF₃DER -5-(4-fluorothiadiazolyl) —CH₂CF₃ DES -5-(4-fluorothiadiazolyl)—OCF₃ DET -5-(4-fluorothiadiazolyl) —Cl DEU -5-(4-fluorothiadiazolyl)—Br DEV -5-(4-fluorothiadiazolyl) —I DEW -5-(4-fluorothiadiazolyl)-n-butyl DEX -5-(4-fluorothiadiazolyl) -n-propyl

TABLE 8

and pharmaceutically acceptable salts thereof, wherein: Compound Ar nDEY -2-(3-chloropyridyl) 2 DEZ -2-(3-fluoropyridyl) 2 DFA-2-(3-methylpyridyl) 2 DFB -2-(3-CF₃-pyridyl) 2 DFC -2-(3-CHF₂-pyridyl)2 DFD -2-(3-hydroxypyridyl) 2 DFE -2-(3-nitropyridyl) 2 DFF-2-(3-cyanopyridyl) 2 DFG -2-(3-bromopyridyl) 2 DFH -2-(3-iodopyridyl) 2DFI -4-(5-chloropyrimidinyl) 2 DFJ -4-(5-methylpyrimidinyl) 2 DFK-4-(5-fluoropyrimidinyl) 2 DFL -2-(3-chloropyrazinyl) 2 DFM-2-(3-methylpyrazinyl) 2 DFN -2-(3-fluoropyrazinyl) 2 DFO-3-(4-chloropyridazinyl) 2 DFP -3-(4-methylpyridazinyl) 2 DFQ-3-(4-fluoropyridazinyl) 2 DFR -5-(4-chlorothiadiazolyl) 2 DFS-5-(4-methylthiadiazolyl) 2 DFT -5-(4-fluorothiadiazolyl) 2 DFU-2-(3-chloropyridyl) 3 DFV -2-(3-fluoropyridyl) 3 DFW-2-(3-methylpyridyl) 3 DFX -2-(3-CF₃-pyridyl) 3 DFY -2-(3-CHF₂-pyridyl)3 DFZ -2-(3-hydroxypyridyl) 3 DGA -2-(3-nitropyridyl) 3 DGB-2-(3-cyanopyridyl) 3 DGC -2-(3-bromopyridyl) 3 DGD -2-(3-iodopyridyl) 3DGE -4-(5-chloropyrimidinyl) 3 DGF -4-(5-methylpyrimidinyl) 3 DGG-4-(5-fluoropyrimidinyl) 3 DGH -2-(3-chloropyrazinyl) 3 DGI-2-(3-methylpyrazinyl) 3 DGJ -2-(3-fluoropyrazinyl) 3 DGK-3-(4-chloropyridazinyl) 3 DGL -3-(4-methylpyridazinyl) 3 DGM-3-(4-fluoropyridazinyl) 3 DGN -5-(4-chlorothiadiazolyl) 3 DGO-5-(4-methylthiadiazolyl) 3 DGP -5-(4-fluorothiadiazolyl) 3

4.17 DEFINITIONS

As used herein, the terms used above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include 5-methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonly and -n-decyl.Representative branched —(C₁-C₁₀)alkyls include -isopropyl, -sec-butyl,-isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl and 3,3-dimethylbutyl, -isopropyl, -sec-butyl,-isobutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbutyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond.

Representative straight chain and branched (C₂-C₁₀)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl,-3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, 1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl,-1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl,-1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at lease onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and-cyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₈-C₁₄)bicycloalkyls include -indanyl,-1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl,-perhydronaphthyl and the like.

“—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated ring.Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl,-1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthreneyl,-1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl,perhydrophenanthrenyl and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms.

Representative (C₅-C₁₀)cycloalkenyls include -cyclopentenyl,-cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl, -cycloheptenyl,-cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl,-cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl -cyclononadienyl,-cyclodecenyl, -cyclodecadienyl and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls include-indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,-1,2,7,8-tetrahydronaphthalenyl and the like.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl and the like.

“—(C₃-C₇)heterocycle” or “—(C₃-C₇)heterocyclo” means a 3- to 7-memberedmonocyclic heterocyclic ring which is either saturated, unsaturatednon-aromatic, or aromatic. A 3-membered —(C₃-C₇)heterocycle can containup to 3 heteroatoms, and a 4- to 7-membered —(C₃-C₇)heterocycle cancontain up to 4 heteroatoms. Each heteroatom is independently selectedfrom nitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The —(C₃-C₇)heterocycle can be attached via anitrogen, sulfur, or carbon atom. Representative —(C₃-C₇)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“—(C₃-C₅)heterocycle” or “—(C₃-C₅)heterocyclo” means a 3- to 5-memberedmonocyclic heterocyclic ring which is either saturated, unsaturatednon-aromatic, or aromatic. A 3-membered —(C₃-C₇)heterocycle can containup to 3 heteroatoms, and a 4- to 5-membered —(C₃-C₅)heterocycle cancontain up to 4 heteroatoms. Each heteroatom is independently selectedfrom nitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The —(C₃-C₇)heterocycle can be attached via anitrogen, sulfur, or carbon atom. Representative —(C₃-C₇)heterocyclesinclude furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl,pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl and the like.

“—(C₇-C₁₀)bicycloheterocycle” or “—(C₇-C₁₀)bicycloheterocyclo” means a7- to 10-membered bicyclic, heterocyclic ring which is either saturated,unsaturated non-aromatic, or aromatic. A —(C₇-C₁₀)bicycloheterocyclecontains from 1 to 4 heteroatoms independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The (C₇-C₁₀)bicycloheterocycle can be attached via a nitrogen,sulfur, or carbon atom. Representative —(C₇-C₁₀)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl and the like.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“—(C₅-C₁₀)heteroaryl” means an aromatic heterocycle ring of 5 to 10members, including both mono- and bicyclic ring systems, wherein atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen and sulfur. Oneor both of the —(C₅-C₁₀)heteroaryl's rings contain at least one carbonatom. Representative (C₅-C₁₀)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl,phthalazinyl, and quinazolinyl.

“-Halogen” or “-Halo” means —F, —Cl, —Br or —I.

The phrase “2-(3-chloropyridyl)” means

The phrase “2-(3-fluoropyridyl)” means

The phrase “2-(3-methylpyridyl)” means

The phrase “2-(3-CF₃-methylpyridyl)” means

The phrase “2-(3-CHF₂-methylpyridyl)” means

The phrase “2-(3-hydroxypyridyl)” means

The phrase “2-(3-nitropyridyl)” means

The phrase “2-(3-cyanopyridyl)” means

The phrase “2-(3-bromopyridyl)” means

The phrase “2-(3-iodopyridyl)” means

The phrase “4-(5-chloropyrimidinyl)” means

The phrase “4-(5-methylpyrimidinyl)” means

The phrase “4-(5-fluoropyrimidinyl)” means

The phrase “2-(3-chloropyrazinyl)” means

The phrase “2-(3-methylpyrazinyl)” means

The phrase “2-(3-fluoropyrazinyl)” means

The phrase “3-(4-chloropyridazinyl)” means

The phrase “3-(4-methylpyridazinyl)” means

The phrase “3-(4-fluoropyridazinyl)” means

The phrase “5-(4-chlorothiadiazolyl)” means

The phrase “5-(4-methylthiadiazolyl)” means

The phrase “5-(4-fluorothiadiazolyl)” means

The phrase “pyridyl group” in connection with the CyanoiminopiperazineCompounds of formula (I), (Ia), and (Ib) means

wherein R₁, R₂, and n are defined above for the CyanoiminopiperazineCompounds of formula (I), (Ia), and (Ib).

The phrase “pyridyl group” in connection with the CyanoiminopiperazineCompounds of formula (Ic) means

wherein R¹¹, R₁₂, and q are defined above for the CyanoiminopiperazineCompounds of formula (Ic).

The phrase “pyrazinyl group” in connection with the CyanoiminopiperazineCompounds of formula (II) means

wherein R₁, R₂, and n are defined above for the CyanoiminopiperazineCompounds of formula (II).

The phrase “pyrazinyl group” in connection with the CyanoiminopiperazineCompounds of formula (IIa) means

wherein R₁, R₂, and q are defined above for the CyanoiminopiperazineCompounds of formula (IIa).

The phrase “pyrimidinyl group” in connection with theCyanoiminopiperazine compounds of formula (I), (IIIa), and (IIIb) means

wherein R₁, R₂, and n are defined above for the CyanoiminopiperazineCompounds of formula (III), (IIIa), and (IIIb).

The phrase “pyrimidinyl group” in connection with theCyanoiminopiperazine Compounds of formula (IIIc) means

wherein R₁₁, R₁₂, and q are defined above for the CyanoiminopiperazineCompounds of formula (Ic).

The phrase “pyridizanyl group” in connection with theCyanoiminopiperazine Compounds of formula (IV) means

wherein R₁, R₂, and n are defined above for the CyanoiminopiperazineCompounds of formula (IV).

The phrase “pyridizanyl group” in connection with theCyanoiminopiperazine Compounds of formula (IVa) means

wherein R₁₁, R₁₂, and q are defined above for the CyanoiminopiperazineCompounds of formula (IVa).

The phrase “thiadiazolyl group” means

wherein R₁ is defined above for the Cyanoiminopiperazine Compounds offormula (V).

The phrase “benzothiazolyl group” means

wherein R⁸ and s are defined above for the CyanoiminopiperazineCompounds of formulas (VI) and (VII).

The phrase “benzoimidazolyl group” means

wherein R⁸ and s are defined above for the CyanoiminopiperazineCompounds of formulas (VI) and (VII).

The phrase “benzooxazolyl group” means

wherein R⁸ and s are defined above for the CyanoiminopiperazineCompounds of formulas (VI) and (VII).

The phrase “(R⁹)-phenyl group” means

The phrase “phenethyl group” means an ethylene group attached to aterminal Ar₂ group, wherein one or each of two hydrogens of the ethylenegroup can optionally be substituted with an R⁴ group. A phenethyl groupis depicted below

wherein R⁴, Ar₂, and t are defined above for the CyanoiminopiperazineCompounds of formula (VI).

The phrase “phenpropyl group” an n-propylene group attached to aterminal Ar₂ group, wherein one or each of two hydrogens of then-propylene group can optionally be substituted with an R⁴ group. Aphenpropyl group is depicted below

wherein R⁴, Ar₂, and t are defined above for the CyanoiminopiperazineCompounds of formula (VII).

The term “animal,” includes, but is not limited to, a cow, monkey,horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit,guinea pig and human.

The phrase “pharmaceutically acceptable salt,” as used herein, is a saltformed from an acid and a basic nitrogen group of one of theCyanoiminopiperazine Compounds. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, lartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from aCyanoiminopiperazine Compound having an acidic functional group, such asa carboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

When a first group is “substituted with one or more” second groups, eachof one or more of the first group's hydrogen atoms is replaced with asecond group. In one embodiment, each carbon atom of a first group isindependently substituted with one or two second groups. In anotherembodiment, each carbon atom of a first group is independentlysubstituted with only one second group.

The term “UI” means urinary incontinence.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “DIEA” means diisopropylethylamine.

The term “DMSO” means dimethyl sulfoxide.

The term “DMF” means dimethyl formamide.

The term “DCM” means dichloromethane.

The phrase “treatment of” and “treating” includes the amelioration orcessation of a Condition or a symptom thereof.

The phrase “prevention of” and “preventing” includes the avoidance ofthe onset of a Condition or a symptom thereof.

4.18 Methods for Making the Cyanoiminopiperazine Compounds

The Cyanoiminopiperazine Compounds can be made using conventionalorganic synthesis or by the following illustrative methods shown in theschemes below. The Cyanoiminopiperazine Compounds wherein A is NR⁴ canbe obtained by the following illustrative methods shown below in SchemeA:

wherein R³, R⁴, R⁶, and m are defined above for the CyanoiminopiperazineCompounds and Ar is:

wherein R¹, R² and n are defined above.

A compound of formula A is reacted with a compound of formula B in anaprotic organic solvent such as diethyl ether, di-n-propyl ether,tetrahydrofuran, methylene chloride, or toluene at a temperature rangingfrom about room temperature to about the reflux temperature of thesolvent for a period of about 0.5 h to about 24 h to provide aCyanoiminopiperazine Compound wherein A is NR⁴. In one embodiment, theaprotic organic solvent is di-n-propyl ether. In another embodiment, areaction mixture of di-n-propyl ether, a compound of formula A and acompound of formula B is heated at a temperature of about 70° to about80° C. In another embodiment, the reaction mixture of di-n-propyl ether,a compound of formula A and a compound of formula B is heated at atemperature of about at 75° C. for about 12 h.

Compounds of formula A can be obtained as shown below in Scheme B:

An amine of formula NHR⁶R⁴, wherein R⁴ and R⁶ are defined above, isreacted with diphenylcyanocabonimidate (commercially available fromSigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in an aproticsolvent such as diethyl ether, di-n-propyl ether, tetrahydrofuran,methylene chloride, or toluene to provide the compound of formula A. Inone embodiment, the aprotic solvent is DCM and the reaction mixture ofNHR⁶R⁴ and diphenylcyaiocabonimidate is allowed to react at about roomtemperature. In another embodiment, the aprotic solvent is toluene andthe reaction mixture of NHR⁶R⁴ and diphenylcyanocabonimidate is allowedto react at about 110° C. The NHR⁶R⁴ and diphenylcyanocabonimidate istypically allowed to react for a period of about 0.5 h to about 24 h.Typically the compound of formula A is used without furtherpurification.

Compounds of formula B can be obtained as shown below in Scheme C:

wherein R¹, R², R³, m, and n are defined above and X is a halogen. Inone embodiment, X is bromide, chloride or iodide.

A compound of formula C₁-C₅ is reacted with a compound of formula D inan aprotic solvent in the presence of DIEA or triethylamine, optionallywith heating, to provide compound B. Compound B is isolated from thereaction mixture and purified. In one embodiment, the reaction ispurified using column chromatography or recrystallization. Compounds offormula C₁-C₅ and D are commercially available or can be prepared bymethods well known to those skilled in the art. The compound of formulaD wherein m is 0 is commercially available from Sigma-Aldrich, St.Louis, Mo. (www.sigma-aldrich.com).

The Cyanoiminopiperazine Compounds wherein A is —O— can be obtained asshown below in Scheme D.

wherein R³, R⁶, m, and Ar are defined above for the CyanoiminopiperazineCompounds.

A compound of formula B is reacted with a compound of formula E toprovide the Cyanoiminopiperazine Compounds wherein A is —O—.Representative procedures for reacting a compound of formula B with acompound of formula E are provided in T. D. Aicher et al., J. Med. Chem.43(2):236-49 (2000) and German Patent No. 3336409.

The compound of formula E can be obtained as shown below in Scheme E.

wherein R⁶ is defined above.

The compound of formula E can be obtained by reacting a compound offormula F with cyanamide. Representative procedures for obtaining acompound of formula E from a compound of formula F are provided in R. L.Webb et al., J. Heterocycl. Chem. 19(5):1205-1206 (1982) and U.S. Pat.No. 4,285,878 to Labaw et al. The compound of formula F can be obtainedas shown below in Scheme F.

wherein R⁶ is defined above.

The compound of formula F can be obtained by reacting a compound offormula G with PCl₅. A representative procedure for obtaining a compoundof formula F from a compound of formula G is provided in R. L. Webb etal., J. Heterocycl. Chem. 19(5):1205-1206 (1982).

The compound of formula G can be obtained by reacting a compound offormula R⁶—OH with COCl₂, triphosgene, or CO and a Pd catalyst asdescribed in U.S. Pat. No. 6,175,017 to H. Buyschi et al.; A. Gode etal., Chemistry-A European Journal 6(19):3522-30 (2000); or H. Yasuda etal., Organometallics, 21(6):1216-20 (2002), respectively. Compounds offormula R⁶—OH are commercially available or can be prepared by methodswell known to those skilled in the art.

The Cyanoiminopiperazine Compounds wherein A is —S— can be obtained asshown below in Scheme G.

wherein R⁶, R³, m, and Ar are defined above and R¹⁰ is —SCH₃ or —O—C₆H₅.

A compound of formula B is reacted with a compound of formula H toprovide the Cyanoiminopiperazine Compounds wherein A is —S—.Representative procedures for reacting a compound of formula B with acompound of formula H are provided in T. D. Aicher et al., J. Med. Chem.43(2):236-49 (2000) and Ger. Patent No. 3336409. The compound of formulaH can be obtained as shown below in Scheme H.

wherein R⁶ and R¹⁰ are defined above.

A thiol of formula R⁶SH is reacted with a compound of formula J toprovide the compound of formula H. Representative procedures forobtaining compounds of formula J and for obtaining the compound offormula H by reacting a thiol with a compound of formula J are providedin R. L. Webb et al., J. Heterocycl. Chem., 24(1):275-78 (1987); I. Reidet al., Liebigs Ann. Chem. 6:599-601 (1988); and L. S. Wittenbrook etal., J. Heterocycl. Chem. 12(1):37-42 (1975). Compounds of formula R⁶—SHare commercially available or can be prepared by methods well known tothose skilled in the art. The Cyanoiminopiperazine Compounds of formulaVI and VII can be obtained as described below in Scheme I.

An amine of formula I or an amine of formula J is reacted withdiphenylcyariocabonimidate (commercially available from Sigma-Aldrich,St. Louis, Mo. (www.sigma-aldrich.com)) in an aprotic solvent such asdiethyl ether, di-n-propyl ether, tetrahydrofuran, methylene chloride,or toluene to provide the compound of formula K or a compound of formulaL, respectively. In one embodiment, the aprotic solvent is DCM and thereaction mixture of the amine of formula I or the amine of formula J anddiphenylcyanocabonimidate is allowed to react at about room temperature.In another embodiment, the aprotic solvent is toluene and the reactionmixture of the amine of formula I or the amine of formula J anddiphenylcyanocabonimidate is allowed to react at about 110° C. The amineof formula I or the amine of formula J and diphenylcyanocabonimidate istypically allowed to react for a period of about 0.5 h to about 24 h.Typically the compound of formula K or the compound of formula L is usedwithout further purification.

The compound of formula K or the compound of formula L is then reactedwith a compound of formula B, obtained as described above in Scheme B,according to the procedure described above in Scheme A to provide theCyanoiminopiperazine Compound of formula (VI) or (VII), respectively.

4.19 Therapeutic Uses of the Cyanoiminopiperazine Compounds

In accordance with the invention, the Cyanoiminopiperazine Compounds areadministered to an animal in need of treatment or prevention of pain,UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression.

In one embodiment, an effective amount of a CyanoiminopiperazineCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting VR1. Examples of conditions that are treatableor preventable by inhibiting VR1 include, but are not limited to, pain,UI, an ulcer, IBD, and IBS.

In another embodiment, an effective amount of a CyanoiminopiperazineCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR5. Examples of conditions that aretreatable or preventable by inhibiting mGluR5 include, but are notlimited to, pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, and psychosis.

In another embodiment, an effective amount of a CyanoiminopiperazineCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR1. Examples of conditions that aretreatable or preventable by inhibiting mGluR1 include, but are notlimited to, pain, UL, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, and depression.

The Cyanoiminopiperazine Compounds can be used to treat or prevent acuteor chronic pain. Examples of pain treatable or preventable using theCyanoiminopiperazine Compounds include, but are not limited to, cancerpain, central pain, labor pain, myocardial infarction pain, pancreaticpain, colic pain, post-operative pain, headache pain, muscle pain, painassociated with intensive care, arthritic pain, neuropathic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

The Cyanoiminopiperazine Compounds can also be used for inhibiting,preventing, or treating pain associated with inflammation or with aninflammatory disease in an animal. The pain to be inhibited, treated orprevented may be associated with inflammation associated with aninflammatory disease, which can arise where there is an inflammation ofthe body tissue, and which can be a local inflammatory response and/or asystemic inflammation. For example, the Cyanoiminopiperazine Compoundscan be used to inhibit, treat, or prevent pain associated withinflammatory diseases including, but not limited to: organ transplantrejection; reoxygenation injury resulting from organ transplantation(see Grupp et al., J. Mol. Cell Cardiol. 31:297-303 (1999)) including,but not limited to, transplantation of the heart, lung, liver, orkidney; chronic inflammatory diseases of the joints, includingarthritis, rheumatoid arthritis, osteoarthritis and bone diseasesassociated with increased bone resorption; inflammatory lung diseases,such as asthma, adult respiratory distress syndrome, and chronicobstructive airway disease; inflammatory diseases of the eye, includingcorneal dystrophy, trachoma, onchocerciasis, uveitis, sympatheticophthalmitis and endophthalmitis; chronic inflammatory diseases of thegum, including gingivitis and periodontitis; tuberculosis; leprosy;inflammatory diseases of the kidney, including uremic complications,glomerulonephritis and nephrosis; inflammatory diseases of the skin,including sclerodermatitis, psoriasis and eczema; inflammatory diseasesof the central nervous system, including chronic demyelinating diseasesof the nervous system, multiple sclerosis, AIDS-relatedneurodegeneration and Alzheimer s disease, infectious meningitis,encephalomyelitis, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis and viral or autoimmune encephalitis;autoimmune diseases, including Type I and Type II diabetes mellitus;diabetic complications, including, but not limited to, diabeticcataract, glaucoma, retinopathy, nephropathy (such as microaluminuriaand progressive diabetic nephropathy), polyneuropathy, mononeuropathies,autonomic neuropathy, gangrene of the feet, atherosclerotic coronaryarterial disease, peripheral arterial disease, nonketotichyperglyceniic-hyperosmolar coma, foot ulcers, joint problems, and askin or mucous membrane complication (such as an infection, a shin spot,a candidal infection or necrobiosis lipoidica diabeticorum);immune-complex vasculitis, and systemic lupus erythematosus (SLE);inflammatory diseases of the heart, such as cardiomyopathy, ischemicheart disease hypercholesterolemia, and atherosclerosis; as well asvarious other diseases that can have significant inflammatorycomponents, including preeclampsia, chronic liver failure, brain andspinal cord trauma, and cancer. The Cyanoiminopiperazine Compounds canalso be used for inhibiting, treating, or preventing pain associatedwith inflammatory disease that can, for example, be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is adminstered as a treatment forcancer.

The Cyanoiminopiperazine Compounds can be used to treat or prevent UI.Examples of UI treatable or preventable using the CyanoiminopiperazineCompounds include, but are not limited to, urge incontinence, stressincontinence, overflow incontinence, neurogenic incontinence, and totalincontinence.

The Cyanoiminopiperazine Compounds can be used to treat or prevent anulcer. Examples of ulcers treatable or preventable using theCyanoiminopiperazine Compounds include, but are not limited to, aduodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer,or a stress ulcer.

The Cyanoiminopiperazine Compounds can be used to treat or prevent IBD,including Crohn's disease and ulcerative colitis.

The Cyanoiminopiperazine Compounds can be used to treat or prevent IBS.Examples of IBS treatable or preventable using the CyanoiminopiperazineCompounds include, but are not limited to, spastic-colon-type IBS andconstipation-predominant IBS.

The Cyanoiminopiperazine Compounds can be used to treat or prevent anaddictive disorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and EatingDisorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse,Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence,Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-InducedMood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder, Alcohol-Related Disordernot otherwise specified (NOS), Alcohol Intoxication, and AlcoholWithdrawal.

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine

Dependence, Amphetamine Abuse, Amphetamine Intoxication, AmphetamineWithdrawal, Amphetamine Intoxication Delirium, Amphetamine-InducedPsychotic Disorder with delusions, Amphetamine-Induced PsychoticDisorders with hallucinations, Amphetamine-Induced Mood Disorder,Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced SexualDysfunction, Amphetamine-Induced Sleep Disorder, Amphetamine RelatedDisorder not otherwise specified (NOS), Amphetamine Intoxication, andAmphetamine Withdrawal.

Cannabis-related disorders include, but are not limited to, CannabisDependence, Cannabis Abuse, Cannabis Intoxication, Cannabis IntoxicationDelirium, Cannabis-Induced Psychotic Disorder with delusions,Cannabis-Induced Psychotic Disorder with hallucinations,Cannabis-Induced Anxiety Disorder, Cannabis Related Disorder nototherwise specified (NOS), and Cannabis Intoxication.

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder,Cocaine Related Disorder not otherwise specified (NOS), CocaineIntoxication, and Cocaine Withdrawal.

Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder with delusions,Hallucinogen-Induced Psychotic Disorders with hallucinations,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-InducedSleep Disorder, Hallucinogen Related Disorder not otherwise specified(NOS), Hallucinogen Intoxication, and Hallucinogen Persisting PerceptionDisorder (Flashbacks).

Inhalant-related disorders include, but are not limited to, InhalantDependence, Inhalant Abuse, Inhalant Intoxication, Inhalant IntoxicationDelirium, Inhalant-Induced Psychotic Disorder with delusions,Inhalant-Induced Psychotic Disorder with hallucinations,Inhalant-Induced Anxiety Disorder, Inhalant Related Disorder nototherwise specified (NOS), and Inhalant Intoxication.

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Related Disorder not otherwise specified (NOS),Opioid Intoxication, and Opioid Withdrawal.

The Cyanoiminopiperazine Compounds can be used to treat or preventParkinson's disease and parkinsonism and the symptoms associated withParkinson's disease and parkinsonism, including but not limited to,bradykinesia, muscular rigidity, resting tremor, and impairment ofpostural balance.

The Cyanoiminopiperazine Compounds can be used to treat or preventgeneralized anxiety or severe anxiety and the symptoms associated withanxiety, including but not limited to, restlessness; tension;tachycardia; dyspnea; depression, including chronic “neurotic”depression; panic disorder; agoraphobia and other specific phobias;eating disorders; and personality disorders.

The Cyanoiminopiperazine Compounds can be used to treat or preventepilepsy, including but not limited to, partial epilepsy, generalizedepilepsy, and the symptoms associated with epilepsy, including but notlimited to, simple partial seizures, Jacksonian seizures, complexpartial (psychomotor) seizures, convulsive seizures (grand mal ortonic-clonic seizures), petit mal (absence) seizures, and statusepilepticus.

The Cyanoiminopiperazine Compounds can be used to treat or preventstrokes, including but not limited to, ischemic strokes and hemorrhagicstrokes.

The Cyanoiminopiperazine Compounds can be used to treat or prevent aseizure, including but not limited to, infantile spasms, febrileseizures, and epileptic seizures.

The Cyanoiminopiperazine Compounds can be used to treat or prevent apruritic condition, including but not limited to, pruritus caused by dryskin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritusvulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis,drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The Cyanoiminopiperazine Compounds can be used to treat or preventpsychosis, including but not limited to, schizophrenia, includingparanoid schizophrenia, hebephrenic or disorganized schizophrenia,catatonic schizophrenia, undifferentiated schizophrenia, negative ordeficit subtype schizophrenia, and non-deficit schizophrenia; adelusional disorder, including erotomanic subtype delusional disorder,grandiose subtype delusional disorder, jealous subtype delusionaldisorder, persecutory subtype delusional disorder, and somatic subtypedelusional disorder; and brief psychosis.

The Cyanoiminopiperazine Compounds can be used to treat or prevent acognitive disorder, including but not limited to, delirium and dementiasuch as multi-infarct dementia, dementia pugilistica, dimentia caused byAIDS, and dementia caused by Alzheimer's disease.

The Cyanoiminopiperazine Compounds can be used to treat or prevent amemory deficiency, including but not limited to, dissociative amnesiaand dissociative fugue.

The Cyanoiminopiperazine Compounds can be used to treat or preventrestricted brain function, including but not limited to, that caused bysurgery or an organ transplant, restricted blood supply to the brain, aspinal cord injury, a head injury, hypoxia, cardiac arrest, orhypoglycemia.

The Cyanoiminopiperazine Compounds can be used to treat or preventHuntington's chorea.

The Cyanoiminopiperazine Compounds can be used to treat or prevent ALS.

The Cyanoiminopiperazine Compounds can be used to treat or preventretinopathy, including but not limited to, arteriosclerotic retinopathy,diabetic arteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

The Cyanoiminopiperazine Compounds can be used to treat or prevent amuscle spasm.

The Cyanoiminopiperazine Compounds can be used to treat or prevent amigraine.

The Cyanoiminopiperazine Compounds can be used to inhibit, treat orprevent vomiting, including but not limited to, nausea vomiting, dryvomiting (retching), and regurgitation.

The Cyanoiminopiperazine Compounds can be used to treat or preventdyskinesia, including but not limited to, tardive dyskinesia and biliarydyskinesia.

The Cyanoiminopiperazine Compounds can be used to treat or preventdepression, including but not limited to, major depression and bipolardisorder. Applicants believe that the Cyanoiminopiperazine Compounds areantagonists for VR1.

The invention also relates to methods for inhibiting VR1 function in acell, comprising contacting a cell capable of expressing VR1 with aneffective amount of a Cyanoiminopiperazine Compound. This method can beused in vitro, for example, as an assay to select cells that express VR1and, accordingly, are useful as part of an assay to select compoundsuseful for treating or preventing pain, UI, an ulcer, IBD, or IBS. Themethod is also useful for inhibiting VR1 function in a cell in vivo, inan animal, a human in one embodiment, by contacting a cell, in ananimal, with an effective amount of a Cyanoiminopiperazine Compound. Inone embodiment, the method is useful for treating or preventing pain inan animal. In another embodiment, the method is useful for treating orpreventing UI in an animal. In another embodiment, the method is usefulfor treating or preventing an ulcer in an animal. In another embodiment,the method is useful for treating or preventing IBD in an animal. Inanother embodiment, the method is useful for treating or preventing IBSin an animal.

Examples of tissue comprising cells capable of expressing VR1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express VR1 are well known inthe art.

Applicants believe that the Cyanoiminopiperazine Compounds areantagonists for mGluR5.

The invention also relates to methods for inhibiting mGluR5 function ina cell, comprising contacting a cell capable of expressing mGluR5 withan amount of a Cyanoiminopiperazine Compound effective to inhibit mGluR5function in the cell. This method can be used in vitro, for example, asan assay to select cells that express mGluR5 and, accordingly, areuseful as part of an assay to select compounds useful for treating orpreventing pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, or psychosis. The method isalso useful for inhibiting mGluR5 function in a cell in vivo, in ananimal, a human in one embodiment, by contacting a cell, in an animal,with an amount of a (Cyanoiminopiperazine Compound effective to inhibitmGluR5 function in the cell. In one embodiment, the method is useful fortreating or preventing pain in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing an addictivedisorder in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing Parkinson's disease in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing parkinsonism in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing anxiety inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing a pruritic condition in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing psychosis in an animal in need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glialcells of the central nervous system, particularly the brain, especiallyin the nucleus accumbens.

Methods for assaying cells that express mGluR5 are well known in theart.

Applicants believe that the Cyanoiminopiperazine Compounds areantagonists for mGluR1.

The invention also relates to methods for inhibiting mGluR1 function ina cell, comprising contacting a cell capable of expressing mGluR1 withan amount of a Cyanoiminopiperazine Compound effective to inhibit mGluR1function in the cell. This method can be used in vitro, for example, asan assay to select cells that express mGluR1 and, accordingly, areuseful as part of an assay to select compounds useful for treating orpreventing pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression. Themethod is also useful for inhibiting mGluR1 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an amount of a Cyanoiminopiperazine Compound effective toinhibit mGluR1 function in the cell. In one embodiment, the method isuseful for treating or preventing pain in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing UIin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing an addictive disorder in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing Parkinson's disease in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingparkinsonism in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing anxiety in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing epilepsy in an animal in need thereof. In another embodiment,the method is useful for treating or preventing stroke in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a seizure in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a pruriticcondition in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing psychosis in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a cognitive disorder in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing amemory deficit in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing restricted brain function inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing Huntington's chorea in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing ALS in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing dementia in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing retinopathy in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a musclespasm in an animal in need thereof. In another embodiment, the method isuseful for treating or preventing a migraine in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing vomiting in an animal in need thereof. In another embodiment,the method is useful for treating or preventing dyskinesia in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing depression in an animal in need thereof.

Examples of cells capable of expressing mGluR1 include, but are notlimited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are well known in the art.

4.19.1 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Cyanoiminopiperazine Compounds areadvantageously useful in veterinary and human medicine. As describedabove, the Cyanoiminopiperazine Compounds are useful for treating orpreventing pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression in an animal in need thereof.

When administered to an animal, the Cyanoiminopiperazine Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a Cyanoiminopiperazine Compound, can beadministered orally. The Cyanoiminopiperazine Compounds of the inventioncan also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.)and can be administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the CyanoiminopiperazineCompound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of the Cyanoiminopiperazine Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer theCyanoiminopiperazine Compounds locally. This can be achieved, forexample, and not by way of limitation, by local infusion during surgery,topical application, e.g., in conjunction with a wound dressing aftersurgery, by injection, by means of a catheter, by means of a suppositoryor enema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assilastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce theCyanoiminopiperazine Compounds into the central nervous system orgastrointestinal tract by any suitable route, includingintraventricular, intrathecal, and epidural injection, and enema.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Cyanoiminopiperazine

Compounds can be formulated as a suppository, with traditional bindersand excipients such as triglycerides.

In another embodiment, the Cyanoiminopiperazine Compounds can bedelivered in a vesicle, in particular a liposome (see Langer, Science249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the Cyanoiminopiperazine Compounds can bedelivered in a controlled-release system or sustained-release system(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled- orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed.Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of the Cyanoiminopiperazine Compounds, e.g., thespinal column, brain, or gastrointestinal tract, thus requiring only afraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to n animal. Water is a particularlyuseful excipient when the Cyanoiminopiperazine Compound is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule (seee.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Cyanoiminopiperazine Compounds are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

In another embodiment, the Cyanoiminopiperazine Compounds can beformulated for intravenous administration. Typically, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lignocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe Cyanoiminopiperazine Compounds are to be administered by infusion,they can be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where theCyanoiminopiperazine Compounds are administered by injection, an ampuleof sterile water for injection or saline can be provided so that theingredients can be mixed prior to administration.

The Cyanoiminopiperazine Compounds can be administered bycontrolled-release or sustained-release means or by delivery devicesthat are well known to those of ordinary skill in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or more active ingredients using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled- or sustained-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients of the invention. The invention thus encompasses single unitdosage forms suitable for oral administration such as, but not limitedto, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled- or sustained-release. Controlled- or sustained-releasepharmaceutical compositions can have a common goal of improving drugtherapy over that achieved by their non-controlled or non-sustainedcounterparts. In one embodiment, a controlled- or sustained-releasecomposition comprises a minimal amount of a CyanoiminopiperazineCompound to cure or control the condition in a minimum amount of time.Advantages of controlled- or sustained-release compositions includeextended activity of the drug, reduced dosage frequency, and increasedpatient compliance. In addition, controlled- or sustained-releasecompositions can favorably affect the time of onset of action or othercharacteristics, such as blood levels of the CyanoiminopiperazineCompound, and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Cyanoiminopiperazine Compound that promptly produces thedesired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Cyanoiminopiperazine Compoundto maintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of theCyanoiminopiperazine Compound in the body, the CyanoiminopiperazineCompound can be released from the dosage form at a rate that willreplace the amount of Cyanoiminopiperazine Compound being metabolizedand excreted from the body. Controlled- or sustained-release of anactive ingredient can be stimulated by various conditions, including butnot limited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the Cyanoiminopiperazine Compound that is effective in thetreatment or prevention of pain, UI, an ulcer, IBD, IBS, an addictivedisorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke,a seizure, a pruritic condition, psychosis, a cognitive disorder, amemory deficit, restricted brain function, Huntington's chorea, ALS,dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia,or depression and can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays can optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed willalso depend on the route of administration, and the seriousness of thecondition being treated and should be decided according to the judgmentof the practitioner and each patient's circumstances in view of, e.g.,published clinical studies. Suitable effective dosage amounts, however,range from about 10 micrograms to about 2500 milligrams about every 4 h,although they are typically about 100 mg or less. In one embodiment, theeffective dosage amount ranges from about 0.01 milligrams to about 100milligrams of a Cyanoiminopiperazine Compound about every 4 h, inanother embodiment, about 0.020 milligrams to about 50 milligrams aboutevery 4 h, and in another embodiment, about 0.025 milligrams to about 20milligrams about every 4 h. The effective dosage amounts describedherein refer to total amounts administered; that is, if more than oneCyanoiminopiperazine Compound is administered, the effective dosageamounts correspond to the total amount administered.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Cyanoiminopiperazine Compound in vitro, the amount effective forinhibiting the receptor function in a cell will typically range fromabout 0.01 μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/Lto about 2.5 mg/L, in another embodiment, from about 0.01 μg/L to about0.5 mg/L, and in another embodiment, from about 0.01 μg/L to about 0.25mg/L of a solution or suspension of a pharmaceutically acceptablecarrier or excipient. In one embodiment, the volume of solution orsuspension is from about 1 μL to about 1 mL. In another embodiment, thevolume of solution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Cyanoiminopiperazine Compound in vivo, the amount effective forinhibiting the receptor function in a cell will typically range fromabout 0.01 mg to about 100 mg/kg of body weight per day, in oneembodiment, from about 0.1 mg to about 50 mg/kg body weight per day, andin another embodiment, from about 1 mg to about 20 mg/kg of body weightper day.

The Cyanoiminopiperazine Compounds can be assayed in vitro or in vivofor the desired therapeutic or prophylactic activity prior to use inhumans. Animal model systems can be used to demonstrate safety andefficacy.

The present methods for treating or preventing pain, UI, an ulcer, IBD,IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, or depression in an animal in needthereof can further comprise administering to the animal beingadministered a Cyanoiminopiperazine Compound another therapeutic agent.

In one embodiment, the other therapeutic agent is administered in aneffective amount.

The present methods for inhibiting VR1 function in a cell capable ofexpressing VR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR5 function in a cell capable ofexpressing mGluR5 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR1 function in a cell capable ofexpressing mGluR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The other therapeutic agent includes, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroid anti-inflammatory agent,an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker,an anticancer agent, an agent for treating or preventing UI, an agentfor treating or preventing an ulcer, an agent for treating or preventingIBD, an agent for treating or preventing IBS, an agent for treatingaddictive disorder, an agent for treating Parkinson's disease andparkinsonism, an agent for treating anxiety, an agent for treatingepilepsy, an agent for treating a stroke, an agent for treating aseizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, and mixturesthereof.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention, whereanother therapeutic agent is administered to an animal, the effectiveamount of the Cyanoiminopiperazine Compound is less than its effectiveamount would be where the other therapeutic agent is not administered.In this case, without being bound by theory, it is believed that theCyanoiminopiperazine Compounds and the other therapeutic agent actsynergistically to treat or prevent pain, UI, an ulcer, IBD, IBS, anaddictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, or depression.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,traniadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine,ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine,lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixturesthereof.

The other therapeutic agent can also be an agent useful for reducing anypotential side effects of a Cyanoiminopiperazine Compounds. For example,the other therapeutic agent can be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, rnoprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine,indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan,oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine,iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alfa-2a, interferonalfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tanoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine;prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropinw methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide. Examples of useful therapeutic agents for treating orpreventing ALS include, but are not limited to, baclofen, neurotrophicfactors, riluzole, tizanidine, benzodiazepines such as clonazepan anddantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlaflaxine; selectiveserotonin reuptake inhibitors such as fluoxetine, fluvoxamine,paroxetine, and setraline; monoamine oxidase inhibitors such asisocarboxazid, pargyline, phenelzine, and tranylcypromine; andpsychostimulants such as dextroamphetamine and methylphenidate.

A Cyanoiminopiperazine Compound and the other therapeutic agent can actadditively or, in one embodiment, synergistically. In one embodiment, aCyanoiminopiperazine Compound is administered concurrently with anothertherapeutic agent. In one embodiment, a composition comprising aneffective amount of a Cyanoiminopiperazine Compound and an effectiveamount of another therapeutic agent can be administered. Alternatively,a composition comprising an effective amount of a CyanoiminopiperazineCompound and a different composition comprising an effective amount ofanother therapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a Cyanoiminopiperazine Compound isadministered prior or subsequent to administration of an effectiveamount of another therapeutic agent. In this embodiment, theCyanoiminopiperazine Compound is administered while the othertherapeutic agent exerts its therapeutic effect, or the othertherapeutic agent is administered while the CyanuoiminopiperazineCompound exerts its preventative or therapeutic effect for treating orpreventing a Condition.

A composition of the invention is prepared by a method comprisingadmixing a Cyanoiminopiperazine Compound or a pharmaceuticallyacceptable salt and a pharmaceutically acceptable carrier or excipient.Admixing can be accomplished using methods well known for admixing acompound (or salt) and a pharmaceutically acceptable carrier orexcipient. In one embodiment the Cyanoiminopiperazine Compound or thepharmaceutically acceptable salt of the Compound is present in thecomposition in an effective amount.

4.19.2 Kits

The invention encompasses kits that can simplify the administration of aCyanoiminopiperazine Compound to an animal.

A typical kit of the invention comprises a unit dosage form of aCyanoiminopiperazine Compound. In one embodiment, the unit dosage formis a container, which can be sterile, containing an effective amount ofa Cyanoiminopiperazine Compound and a pharmaceutically acceptablecarrier or excipient. The kit can further comprise a label or printedinstructions instructing the use of the Cyanoiminopiperazine Compound totreat pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression. The kitcan also further comprise a unit dosage form of another therapeuticagent, for example, a container containing an effective amount of theother therapeutic agent. In one embodiment, the kit comprises acontainer containing an effective amount of a CyanoiminopiperazineCompound and an effective amount of another therapeutic agent. Examplesof other therapeutic agents include, but are not limited to, thoselisted above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device includes,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not, of course, be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now knownor later developed, which would be within the purview of those skilledin the art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

Examples 1-3 relate to the synthesis of illustrativeCyanoiminopiperazine Compounds.

5.1. Example 1 Synthesis of Compound AAA

2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine (9.78 g, 113.70mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mLof DMSO and the resulting mixture was heated at about 80° C. for about24 h. The reaction mixture was then cooled to room temperature andextracted with a saturated aqueous sodium bicarbonate solution. Theorganic layer was dried, concentrated, and purified using a silica gelcolumn eluted with a gradient elution from ethyl acetate to 2:1 ethylacetate:methanol to provide N-(3-chloropyridin-2-yl)-piperazine(compound 1) as a yellow liquid.

A solution diphenylcyanocarbodimidate (Commercially available fromSigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) (0.5 mmol) and4-tert-butylaniline (0.5 mmol) in 1.5 mL of DCM was stirred at roomtemperature for about 12 h. The mixture was concentrated under reducedpressure to provide compound 2, which was used directly in the next stepwithout further purification.

A solution of compound 2, prepared as described above, and compound 1(0.5 mmol), prepared as described above, in 1.5 mL of2-methoxymethylether was stirred at about 75° C. for about 12 h. Thesolution was cooled to room temperature and purified using direct flashchromatography on a silica gel column eluted with a gradient elutionfrom 1:10 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to provideCompound AAA (62% yield).

The identity of compound AAA was confirmed using ¹H NMR.

Compound AAA: ¹H NMR (CDCl₃) δ 9.19 (dd, J=1.5, 4.7 Hz, 1H), 6.62 (dd,J=1.5, 7.8 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.18 (b, 1H), 7.01 (d, J=8.5Hz, 2H), 6.91 (dd, J=4.7, 7.8 Hz, 1H), 3.58 (m, 4H), 3.34 (m, 4H), 1.33(s, 9H) ppm.

5.2. Example 2 Synthesis of Compound AAI

Compound AAI was prepared by a procedure analogous to that used toprepare Compound AAA except that 4-trifluoromethoxyaniline was used inplace of 4-tert-butylaniline (yield 78%).

The identity of compound AAI was confirmed using ¹H NMR.

Compound AAI: ¹H NMR (CDCl₃) δ 8.19 (dd, J=1.6, 4.7 Hz, 1H), 7.62 (dd,J=1.6, 7.8 Hz, 1H), 7.26 (b, 1H), 7.24 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0Hz, 2H), 6.92 (dd, J=4.7 Hz, 1H), 3.59 (m, 4H), 3.35 (m, 4H) ppm.

5.3. Example 3 Synthesis of Compound AAG

Compound AAG was prepared by a procedure analogous to that used toprepare Compound AAA except that 4-trifluoromethylaniline was used inplace of 4-tert-butylaniline (yield 61%).

The identity of compound AAG was confirmed using ¹H NMR.

Compound AAG: ¹H NMR (CDCl₃) δ 8.19 (dd, J=1.6, 4.7 Hz, 1H), 7.62 (dd,J=1.6, 7.8 Hz, 1H), 7.26 (b, 1H), 7.24 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0Hz, 2H), 6.92 (dd, J=4.7 Hz, 1H), 3.59 (m, 4H), 3.35 (m, 4H) ppm.

5.4. Example 4 Synthesis of Compound DEY

To a solution of 2-(1-cyclohexenyl)-ethylamine 3 (125.2 mg, 1.0 mmol) in2-methoxyethyl ether (2.0 mL) was added diphenylcyanocarbodimidate(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) (238.2 mg, 1.0 mmol) at room temperature. Theresultant reaction mixture was heated to about 80° C. and allowed tostir at 80° C. for about 5 h.(R)-1-(3-chloro-pyridin-2-yl)-3-methylpiperazine 4 (211.6 mg, 1.0 mmol)was added to the reaction mixture and the reaction mixture was heated toabout 140° C. and allowed to stir at about 140° C. for about 12 h. Thereaction mixture was then cooled to room temperature and purified usingflash chromatography on a silica gel column eluted with ethylacetate/hexane (10:90 to 50:50) to provide compound DEY as a slightlyyellow product.

Compound 4 was prepared by a procedure analogous to that used to prepareCompound 1, as described above in Example 1, except that(R)-3-methylpiperazine commercially available from Sigma-Aldrich, St.Louis, Mo. (www.sigma-aldrich.com)) was used in place of piperazine.

The identity of compound DEY was confirmed using ¹H NMR and massspectroscopy (MS).

Compound DEY: ¹H NMR (CDCl₃) δ 8.20 (dd, J=1.8, 4.9 Hz, 1H), 7.63 (dd,J=1.8, 7.8 Hz, 1H), 6.91 (dd, J=4.9, 7.8 Hz, 1H), 5.61 (br, s, 1H), 4.80(m, 1H), 4.32 (m, 1H), 3.80 (m, 3H), 3.63 (m, 2H), 3.42 (m, 1H), 3.10(m, 1H), 3.00 (m, 1H), 2.31 (m, 1H), 2.05 (m, 2H), 1.96 (m, 2H), 1.64(m, 5H), 1.43 (m, 3H) ppm.

MS: m/e 387.6

5.5. Example 5 Binding of Cyanoiminopiperazine Compounds to mGluR5

The following assay can be used to demonstrates CyanoiminopipereazineCompounds that bind to and modulate the activity of mGluR5.

Cell cultures: Primary glial cultures are prepared from cortices ofSprague-Dawley 18 days old embryos. The cortices are dissected and thendissociated by trituration. The resulting cell homogenate is plated ontopoly-D-lysine precoated T175 flasks (BIOCOAT, commercially availablefrom Becton Dickinson and Company Inc. of Franklin Lakes, N.J.) inDulbelcco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25mM HEPES, and supplemented with 15% fetal calf serum (“FCS,”commercially available from Hyclone Laboratories Inc. of Omaha, Nebr.),and incubated at 37° C. and 5% CO₂. After 24 hours, FCS supplementationis reduced to 10%. On day six, oligodendrocytes and microglia areremoved by strongly tapping the sides of the flasks. One day followingthis purification step, secondary astrocyte cultures are established bysubplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at adensity of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, theastrocytes are washed with serum free medium and then cultured in DMEM,without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mLepidermal growth factor (“EGF”), 1 mM sodium pyruvate, and 1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂.The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience15(9):6103-6109 (1995).

Assay Protocol: After 3-5 days incubation with EGF, the astrocytes arewashed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂PO₄, 2 mMCaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”)and loaded with the dye Fluo-4 (commercially available from MolecularProbes Inc. of Eugene, Oreg.) using 0.1 mL of Assay Buffer containingFluo-4 (3 mM final). After 90 minutes of dye loading, the cells are thenwashed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of AssayBuffer. The plates containing the astrocytes are then transferred to aFluorometric Imaging Plate reader (commercially available from MolecularDevices Corporation of Sunnyvale, Calif.) for the assessment of calciummobilization flux in the presence of glutamate and in the presence orabsence of antagonist. After monitoring fluorescence for 15 seconds toestablish a base line, DMSO solutions containing various concentrationsof a Cyanoiminopipereazine Compound diluted in Assay Buffer (0.05 mL of4× dilutions for competition curves) are added to the cell plate andfluorescence is monitored for 2 minutes. 0.05 mL of a 4× glutamatesolution (agonist) is then added to each well to provide a finalglutamate concentration in each well of 10 mM. Plate fluorescence isthen monitored for an additional 60 seconds after agonist addition. Thefinal DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine IC₅₀ value. In eachexperiment, each data point is determined two times. The assay resultswill demonstrate that Cyanoiminopipereazine Compounds bind to andmodulate the activity of mGluR5.

5.6 EXAMPLE 6 Binding of Cyanoiminopiperazine Compounds to mGluR5

Alternatively, the following assay can be used to demonstrate that aCyanoiminopiperazine Compound binds to and modulates the activity ofmGluR5.

40,000 CHO-rat mGluR5 cells/well are plated into 96 well plate (Costar3409, Black, clear bottom, 96 well, tissue culture treated) for anovernight incubation in Dulbecco's Modified Eagle's Medium (DMEM, pH7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500ug/mL Geneticin. CHO-rat mGluR5 cells are washed and treated withOptimem medium and were incubated for 1-4 hours prior to loading cells.Cell plates are washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mMMgCl₂, 700 μM Na H₂PO₄, 2 mM CaCl₂, 5 mM NaHCO₃, 8 mM Hepes, and 10 mMglucose, pH 7.4) and incubated with 31M Fluo 4 (commercially availablefrom Molecular probes Inc. of Eugene, Oreg.) in 0.1 mL of loadingbuffer. After 90 minutes of dye loading, the cells are washed twice with0.2 mL loading buffer and resuspended in 0.1 mL loading buffer.

The plates containing the CHO-rat mGluR5 cells are transferred to aFluorometric Imaging Plate Reader (FLIPR) (commercially available fromMolecular Devices Corporation of Sunnyvale, Calif.) for the assessmentof calcium mobilization flux in the presence of glutamate and in thepresence or absence of test compounds. After monitoring fluorescence for15 seconds to establish a baseline, DMSO solutions containing variousconcentrations of the test compound diluted in loading buffer (0.05 mLof 4× dilutions for the competition curves) are added to the cell plateand fluorescence was monitored for 2 minutes. 0.05 mL of 4× glutamatesolution (agonist) is then added to each well to provide a finalglutamate concentration in each well of 10 uM. Plate fluorescence isthen monitored for an additional 60 seconds after agonist addition. Thefinal DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine the IC₅₀ value. In eachexperiment, each data point is determined at least two times.

5.7. Example 7—In Vivo Assays for Prevention or Treatment of Pain

Test Animals Each experiment uses rats weighing between 200-260 g at thestart of the experiment. The rats are group-housed and have free accessto food and water at all times, except prior to oral administration of aCyanoiminopiperazine Compound when food is removed for 16 hours beforedosing. A control group acts as a comparison to rats treated with aCyanoiminopiperazine Compound. The control group is administered thecarrier for the Cyanoiminopiperazine Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Cyanoiminopiperazine Compound administered to the test group.

Acute Pain: To assess the actions of the Cyanoiminopiperazine Compoundsfor the treatment or prevention of acute pain the rat tail flick testcan be used. Rats are gently restrained by hand and the tail exposed toa focused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a Cyanoiminopiperazine Compound. Data areexpressed as tail flick latency(s) and the percentage of the maximalpossible effect (% MPE), i.e., 20 seconds, is calculated as follows:

${\% \mspace{11mu} {MPE}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)\end{bmatrix}}{\left( {20\mspace{11mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941). The results show that Cyanoiminopiperazine Compoundsare useful for treating or preventing acute pain.

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain To assess the actions of the CyanoiminopiperazineCompounds for the treatment or prevention of inflammatory pain theFreund's complete adjuvant (“FCA”) model of inflammatory pain is used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (L. Bartho et al., “Involvement ofCapsaicin-sensitive Neurones in Hyperalgesia and Enhanced OpioidAntinociception in Inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacology 342:666-670 (1990)). The left hind paw of each animal isadministered a 50 μL intraplantar injection of 50% FCA. 24 hour postinjection, the animal is assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats are thenadministered a single injection of 1, 3, 10 or 30 mg/Kg of either aCyanoiminopiperazine Compound, 30 mg/Kg of a control selected fromindomethacin, Celebrex or naproxen or carrier. Responses to noxiousmechanical stimuli are then determined 1, 3, 5, and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\% \mspace{11mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}{\mspace{11mu} \;}{PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{Baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}{\mspace{11mu} \;}{PWT}} \right)} \right\rbrack} \times 100}$

The results show that the Cyanoiminopiperazine Compounds are useful fortreating or preventing inflammatory pain.

Neuropathic Pain: To assess the actions of the CyanoiminopiperazineCompounds for the treatment or prevention of neuropathic pain either theSeltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocantherjust distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to l₂ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and a Vetbond surgical glue. Following surgery, the wound areais dusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for the left rear paw of theanimal. Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{11mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}{\mspace{11mu} \;}{PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{Baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}{\mspace{11mu} \;}{PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a CyanoiminopiperazineCompound for the left rear paw of the animal. The animal can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in S. H. Kim, “An Experimental Model for Peripheral NeuropathyProduced by Segmental Spinal Nerve Ligation in the Rat,” Pain50(3):355-363 (1992). The results will show that CyanoiminopiperazineCompounds are useful for treating or preventing neuropathic pain.

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacology Biochemistry and Behavior 31:451-455 (1988).The maximum weight that can be applied to the hind paw is set at 250 gand the end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Only theaffected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

5.8. Example 8—In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be usedto assess the anxiolytic activity of Cyanoiminopipereazine Compounds inrats or mice.

The Elevated Plus Maze Test: The elevated plus maze consists of aplatform with 4 arms, two open and two closed (50×10×50 cm enclosed withan open roof). Rats (or mice) are placed in the center of the platform,at the crossroad of the 4 arms, facing one of the closed arms. Timespent in the open arms vs the closed arms and number of open arm entriesduring the testing period are recorded. This test is conducted prior todrug administration and again after drug administration. Test resultsare expressed as the mean time spent in open arms and the mean number ofentries into open arms. Known anxiolytic drugs increase both the timespent in open arms and number of open arm entries. The elevated plusmaze test is described in Treit, “Animal Models for the Study ofAnti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews9(2):203-222 (1985).

The Shock-Probe Burying Test: For the shock-probe burying test thetesting apparatus consists of a plexiglass box measuring 40×30×40 cm,evenly covered with approximately 5 cm of bedding material (odorabsorbent kitty litter) with a small hole in one end through which ashock probe (6.5 cm long and 0.5 cm in diameter) is inserted. Theplexiglass shock probe is helically wrapped with two copper wiresthrough which an electric current is administered. The current is set at2 mA. Rats are habituated to the testing apparatus for 30 min on 4consecutive days without the shock probe in the box. On test day, ratsare placed in one corner of the test chamber following drugadministration. The probe is not electrified until the rat touches itwith its snout or fore paws, at which point the rat receives a brief 2mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra. The results of this test will demonstrate thatCyanoiminopipereazine Compounds are useful for treating or preventinganxiety.

5.9. Example 9—In Vivo Assays for Prevention or Treatment of anAddictive Disorder

The conditioned place preference test or drug self-administration testcan be used to assess the ability of Cyanoiminopipereazine Compounds toattenuate the rewarding properties of known drugs of abuse.

The Conditioned Place Preference Test: The apparatus for the conditionedplace preference test consists of two large compartments (45×45×30 cm)made of wood with a plexiglass front wall. These two large compartmentsare distinctly different. Doors at the back of each large compartmentlead to a smaller box (36×18×20 cm) box made of wood, painted grey, witha ceiling of wire mesh. The two large compartments differ in terms ofshading (white vs black), level of illumination (the plexiglass door ofthe white compartment is covered with aluminum foil except for a windowof 7×7 cm), texture (the white compartment has a 3 cm thick floor board(40×40 cm) with nine equally spaced 5 cm diameter holes and the blackhas a wire mesh floor), and olfactory cues (saline in the whitecompartment and 1 mL of 10% acetic acid in the black compartment). Onhabituation and testing days, the doors to the small box remain open,giving the rat free access to both large compartments.

The first session that a rat is placed in the apparatus is a habituationsession and entrances to the smaller grey compartment remain open givingthe rat free access to both large compartments. During habituation, ratsgenerally show no preference for either compartment. Followinghabituation, rats are given 6 conditioning sessions. Rats are dividedinto 4 groups: carrier pre-treatment+carrier (control group),Cyanoiminopipereazine Compound pre-treatment+carrier, carrierpre-treatment+morphine, Cyanoiminopipereazine Compoundpre-treatment+morphine. During each conditioning session the rat isinjected with one of the drug combinations and confined to onecompartment for 30 min. On the following day, the rat receives acarrier+carrier treatment and is confined to the other largecompartment. Each rat receives three conditioning sessions consisting of3 drug combination-compartment and 3 carrier-compartment pairings. Theorder of injections and the drug/compartment pairings arecounterbalanced within groups. On the test day, rats are injected priorto testing (30 min to 1 hour) with either morphine or carrier and therat is placed in the apparatus, the doors to the grey compartment remainopen and the rat is allowed to explore the entire apparatus for 20 min.The time spent in each compartment is recorded. Known drugs of abuseincrease the time spent in the drug-paired compartment during thetesting session. If the Cyanoiminopipereazine Compound blocks theacquisition of morphine conditioned place preference (reward), therewill be no difference in time spent in each side in rats pre-treatedwith a Cyanoiminopipereazine Compound and the group will not bedifferent from the group of rats that was given carrier+carrier in bothcompartments. Data will be analyzed as time spent in each compartment(drug combination-paired vs carrier-paired). Generally, the experimentis repeated with a minimum of 3 doses of a CyanoiminopipereazineCompound.

The Drug Self-Administration Test: The apparatus for the drugself-administration test is a standard commercially available operantconditioning chamber. Before drug trials begin rats are trained to pressa lever for a food reward. After stable lever pressing behavior isacquired, rats are tested for acquisition of lever pressing for drugreward. Rats are implanted with chronically indwelling jugular cathetersfor i.v. administration of compounds and are allowed to recover for 7days before training begins. Experimental sessions are conducted dailyfor 5 days in 3 hour sessions. Rats are trained to self-administer aknown drug of abuse, such as morphine. Rats are then presented with twolevers, an “active” lever and an “inactive” lever. Pressing of theactive lever results in drug infusion on a fixed ratio 1 (FR₁) schedule(i.e., one lever press gives an infusion) followed by a 20 second timeout period (signaled by illumination of a light above the levers).Pressing of the inactive lever results in infusion of excipient.Training continues until the total number of morphine infusionsstabilizes to within ±10% per session. Trained rats are then used toevaluate the effect of Cyanoiminopipereazine Compounds pre-treatment ondrug self-administration. On test day, rats are pre-treated with aCyanoiminopipereazine Compound or excipient and then are allowed toself-administer drug as usual. If the Cyanoiminopipereazine Compoundblocks the rewarding effects of morphine, rats pre-treated with theCyanoiminopipereazine Compound will show a lower rate of respondingcompared to their previous rate of responding and compared to excipientpre-treated rats. Data is analyzed as the change in number of druginfusions per testing session (number of infusions during testsession—number of infusions during training session). The results willdemonstrate that Cyanoiminopipereazine Compounds are useful for treatingor preventing an addictive disorder.

5.10. Example 10—Functional Assay for Characterizing mGluR1 AntagonisticProperties

Functional assays for the characterization of mGluR1 antagonisticproperties are well known in the art. For example, the followingprocedure can be used.

cDNA encoding rat mGluR1a receptor is obtained from, e.g., Prof. S,Nakanishi (Kyoto, Japan). It is transiently transfected into HEK-EBNAcells using a procedure described by Schlaeger et al., New Dev. NewAppl. Anim. Cell Techn., Proc. ESACT Meet., 15^(th)á (1998), 105-112 and117-120. [Ca²⁺] measurements are performed on mGluR^(1a) transfectedHEK-EBNA cells after incubation of the cells with Fluo-3 AM (0.5 μMfinal concentration) for 1 hour at 37° C. followed by 4 washes withassay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES. [Ca²⁺]measurements are done using a fluorometric imaging plate reader, e.g.,FLIPR from Molecular Devices Corporation, La Jolla, Calif. 10 μMglutamate as agonist is used to evaluate the potency of the antagonists.Increasing concentrations of antagonists are applied to the cells 5minutes prior to application of the agonist. The inhibition(antagonists) curves are fitted with appropriate software, for example,the four-parameter logistic equation giving IC₅₀ and Hill coefficientusing the iterative nonlinear curve fitting software Origin fromMicrocal Software Inc., Northampton, Mass. The results of this assaywill demonstrate that Cyanoiminopipereazine Compounds bind to andmodulate the activity of mGluR1.

5.11. Example 11—Binding of Cyanoiminopiperazine Compounds to VR1

Methods for assaying compounds capable of inhibiting VR1 are well knownto those skilled in the art, for example, those methods disclosed inU.S. Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 toMcIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al. The resultsof these assays will demonstrate that Cyanoiminopiperazine Compoundsbind to and modulate the activity of VR1.

Binding of Compound DEY to VR1: Assay Protocol

Human VR1 cloning. Human spinal cord RNA (commercially available fromClontech, Palo Alto, Calif.) was used. Reverse transcription wasconducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase(commercially available from Invitrogen, Carlsbad, Calif.) and oligo dTprimers as detailed in its product description. Reverse transcriptionreactions were incubated at 55° C. for 1 h, heat-inactivated at 85° C.for 5 min, and RNase H-treated at 37° C. for 20 min.

Human VR1 cDNA sequence was obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences were removed and flanking exonic sequences were joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human VR1 were designed as follows: forward primer,GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer,GAAGATCTTCGGGGACAGTGACGGTTGGATGT.

PCR of VR1 was performed on one tenth of the Reverse transcriptionreaction mixture using Expand Long Template Polymerase and Expand Buffer2 in a final volume of 50 μL according to the manufacturer'sinstructions (Roche Applied Sciences, Indianapolis, Ind.). Afterdenaturation at 94° C. for 2 min PCR amplification was performed for 25cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68° C. for 3 minfollowed by a final incubation at 72° C. for 7 min to complete theamplification. A PCR product of ˜2.8 kb was gel-isolated using a 1.0%agarose, Tris-Acetate gel containing 1.6 μg/mL of crystal violet andpurified with a S.N.A.P. UV-Free Gel Purification Kit (commerciallyavailable from Invitrogen). The VR1 PCR product was cloned into thepIND/V5-His-TOPO vector (commercially available from Invitrogen)according to the manufacturer's instructions. DNA preparations,restriction enzyme digestions, and preliminary DNA sequencing wereperformed according to standard protocols. Full-length sequencingconfirmed the identity of the human VR1.

Generation of inducible cell lines. Unless noted otherwise, cell culturereagents were purchased from Life Technologies of Rockville, Md.HEK293-EcR cells expressing the ecdysone receptor (commerciallyavailable from Invitrogen) were cultured in Growth Medium (Dulbecco'sModified Eagles Medium containing 10% fetal bovine serum (commerciallyavailable from HYCLONE, Logan, Utah), 1× penicillin/streptomycin, 1×glutamine, 1 mM sodium pyruvate and 400 μg/mL Zeocin (commerciallyavailable from Invitrogen)). The VR1-pIND constructs were transfectedinto the HEK293-EcR cell line using Fugene transfection reagent(commercially available from Roche Applied Sciences, Basel,Switzerland). After 48 h, cells were transferred to Selection Medium(Growth Medium containing 300 μg/mL G418 (commercially available fromInvitrogen)). Approximately 3 weeks later individual Zeocin/G418resistant colonies were isolated and expanded. To identify functionalclones, multiple colonies were plated into 96-well plates and expressionwas induced for 48 h using Selection Medium supplemented with 5 μMponasterone A (“PonA”) (commercially available from Invitrogen). On theday of assay, cells were loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx was measured using a Fluorometric ImagingPlate Reader (“FLIPR”) (commercially available from Molecular DevicesCorp., Sunnyvale, Calif.) as described below. Functional clones werere-assayed, expanded, and cryopreserved.

pH-Based Assay. Two days prior to performing this assay, cells wereseeded on poly-D-lysine-coated 96-well clear-bottom black plates(commercially available from Becton-Dickinson) at 75,000 cells/well ingrowth media containing 5 μM PonA (commercially available fromInvitrogen) to induce expression. On the day of the assay, the plateswere washed with 0.2 mL 1× Hank's Balanced Salt Solution (commerciallyavailable from Life Technologies) containing 1.6 mM CaCl₂ and 20 mMHEPES, pH 7.4 (“wash buffer”), and loaded using 0.1 mL of wash buffercontaining Fluo-4 (3 μM final concentration, commercially available fromMolecular Probes). After 1 h, the cells were washed twice with 0.2 mLwash buffer and resuspended in 0.05 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 3.5 mM CaCl₂and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates were then transferredto a FLIPR (commercially available from Molecular Devices) for assay.Compound DEY was diluted in assay buffer, and 50 mL of the resultantsolution were added to the cell plates and the solution monitored fortwo minutes. The final concentration of Compound DEY ranged from about50 pM to about 3 μM. Agonist buffer (wash buffer titrated with 1N HCl toprovide a solution having a pH of 5.5 when mixed 1:1 with assay buffer)(0.1 mL) was then added to each well, and the plates were incubated for1 additional minute. Data were collected over the entire time course andanalyzed using Excel and Graph Pad Prism. Compound DEY when assayedaccording to this protocol had an IC₅₀ of 196.7±39.8 nM (n+3).

Capsaicin-based Assay. Two days prior to performing this assay, cellswere seeded in poly-D-lysine-coated 96-well clear-bottom black plates(50,000 cells/well) in growth media containing 5 μM PonA (commerciallyavailable from Invitrogen) to induce expression. On the day of theassay, the plates were washed with 0.2 mL 1× Hank's Balanced SaltSolution (commercially available from Life Technologies) containing 1 mMCaCl₂ and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL ofwash buffer containing Fluo-4 (3 μM final). After one hour, the cellswere washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mLof wash buffer. The plates were transferred to a FLIPR (commerciallyavailable from Molecular Devices) for assay. 50 μL of Compound DEYdiluted with assay buffer were added to the cell plates and incubatedfor 2 min. The final concentration of Compound DEY ranged from about 50μM to about 3 μM. Human VR1 was activated by the addition of 50 μL ofcapsaicin (400 nM), and the plates were incubated for an additional 3min. Data were collected over the entire time course and analyzed usingExcel and GraphPad Prism. Compound DEY when assayed according to thisprotocol had an IC₅₀ of 59.4±13.1 nM (n+3).

The results of the pH-based assay and the capsaicin-based assaydemonstrate that Compound DEY, an illustrative CyanoiminopiperazineCompound, binds to and modulates the activity of human VR1.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —NR⁴—, —O—,or —S—; R¹ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo); each R² is independently: (a) -halo, —CN,—OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₃-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or (c) -phenyl, -naphthyl,—(C₁₄)aryl, or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups; each R³ is independently: (a)-halo, —CN, —OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or (c) -phenyl-naphthyl,—(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups; R⁴ is hydrogen, —(C₁-C₆)alkyl,or —O—(C₁-C₆)alkyl; each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸; R⁶ is-phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups; each R⁷ is independently —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₁-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸,—NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or—S(O)₂R⁸; each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂; each halo isindependently —F, —Cl, —Br or —I; n is an integer ranging from 0 to 2;and m is an integer ranging from 0 to
 2. 2. The compound of claim 1,wherein A is —NH—.
 3. The compound of claim 2, wherein: n is 0; m is 0;and R⁶ is phenyl.
 4. The compound of claim 3, wherein the R⁶ phenyl isunsubstituted.
 5. The compound of claim 3, wherein the R⁶ phenyl issubstituted at the 4-position.
 6. The compound of claim 5, wherein theR⁶ phenyl is substituted with a —CF₃ group or an —(C₁-C₆)alkyl,optionally a tert-butyl group or an iso-propyl group.
 7. The compound ofclaim 3, wherein R¹ is chloro or methyl.
 8. The compound of claim 7,wherein the R⁶ phenyl is unsubstituted.
 9. The compound of claim 7,wherein the R⁶ phenyl is substituted at the 4-position.
 10. The compoundof claim 9, wherein the R⁶ phenyl is substituted with a —CF₃ group or an—(C₁-C₆)alkyl, optionally a tert-butyl group or an iso-propyl group. 11.The compound of claim 1, wherein A is —O—.
 12. The compound of claim 1,wherein A is —S—.
 13. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —NR⁴—, —O—,or —S—; each R³ is independently: (a) -halo, —CN, —OH, —NO, or —NH₂; (b)—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle,or —(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or (c) -phenyl, -naphthyl,—(C₁₄)aryl or —(C₅-C₁₀)heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups: R⁴ is hydrogen, —(C₁-C₆)alkyl,or —O—(C₁-C₆)alkyl; each R⁵ is independently —CN, —OH, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸OH, —OR⁸,—COR⁸—C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸; R⁶ is-phenyl, -naphthyl, —(C₃-C₈)cycloalkyl, —(C₁₄)aryl, or—(C₅-C₁₀)heteroaryl, each of which is unsubstituted or substituted withone or more R⁷ groups; each R⁷ is independently —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —(C₃-C₅)heterocycle, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R⁸)₂, —CH═NR⁸,—NR⁸OH, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸, —SR⁸, —S(O)R⁸, or—S(O)₂R⁸; each R⁸ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₃-C₅)heterocycle, —C(halo)₃, —CH₂(halo), or —CH(halo)₂; R¹¹ is-hydrogen, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo); each R¹² is independently: (a) -halo, —CN,—OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, —(C₃-C₇)heterocycle, or—(C₇-C₁₀)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or (c)-phenyl, -naphthyl,—(C₁₄)aryl, or —(C₅-C₁₀))heteroaryl, each of which is unsubstituted orsubstituted with one or more R⁷ groups; each halo is independently —F,—Cl, —Br or —I; q is an integer ranging from 0 to 2; and m is an integerranging from 0 to
 2. 14. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, C(halo)₃,—CH(halo)₂, or —CH₂(halo); each R² is independently: (a) -halo, —CN,—OH, —NO₂, or —NH₂; (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₉-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R⁵ groups; or (c) -phenyl, -naphthyl,—(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with one or more R₆ groups; each R³ isindependently: (a) -halo, —CN, —OH, —NO₂, or —NH₂: (b) —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R⁵ groups; or(c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered) heteroaryl,each of which is unsubstituted or substituted with one or more R⁶groups; each R⁴ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo); each R⁵is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃,—NO₂, —N(R⁸)₂, —CH═NR⁸, —NR⁸H, —OR⁸, —COR⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —SR⁸, —S(O)R⁸, or —S(O)₂R⁸; each R⁶ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇; each R⁷ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₁-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo); each R⁸is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇, —NR₇OH,—OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;each R¹¹ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each halo isindependently —F, —Cl, —Br, or —I; m is 0 or 1; n is an integer rangingfrom 0 to 3: o is an integer ranging from 0 to 4; p is an integerranging from 0 to 2; q is an integer ranging from 0 to 6; r is aninteger ranging from 0 to 5; s is an integer ranging from 0 to 4; t isan integer ranging from 0 to 2; and u is 0 or
 1. 15. A compositioncomprising an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 16. A composition comprising aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim 13 and a pharmaceutically acceptable carrier orexcipient.
 17. A composition comprising an effective amount of thecompound or a pharmaceutically acceptable salt of the compound of claim14 and a pharmaceutically acceptable carrier or excipient.
 18. A methodfor treating pain in an animal, comprising administering to an animal inneed thereof an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim
 1. 19. A method for treatingpain in an animal, comprising administering to an animal in need thereofan effective amount of the compound or a pharmaceutically acceptablesalt of the compound of claim
 13. 20. A method for treating pain in ananimal, comprising administering to an animal in need thereof aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim
 14. 21. A method for inhibiting VR1 function ina cell, comprising contacting a cell capable of expressing VR1 with aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim
 1. 22. A method for inhibiting VR1 function ina cell, comprising contacting a cell capable of expressing VR1 with aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim
 13. 23. A method for inhibiting VR1 function ina cell, comprising contacting a cell capable of expressing VR1 with aneffective amount of the compound or a pharmaceutically acceptable saltof the compound of claim
 14. 24. A method for preparing a composition,the method comprising admixing a compound or a pharmaceuticallyacceptable salt of the compound of claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 25. A method for preparing acomposition, the method comprising admixing a compound or apharmaceutically acceptable salt of the compound of claim 13 and apharmaceutically acceptable carrier or excipient.
 26. A method forpreparing a composition, the method comprising admixing a compound or apharmaceutically acceptable salt of the compound of claim 14 and apharmaceutically acceptable carrier or excipient.